MIP-1α, MIP-1β

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MIP-1, MIP-1 Barbara Sherry* and Giovanni Franchin The Picower Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA * corresponding author tel: 516-562-9451, fax: 516-365-5090, e-mail: [email protected] DOI: 10.1006/rwcy.2000.11005.

SUMMARY MIP-1 and MIP-1 are members of the CC subgroup of the chemokine family. Although these two peptides are structurally and functionally related to one another, as well as to other CC chemokine family members, each exhibits distinct features which allows it to independently regulate specific aspects of the host inflammatory response. MIP-1 and MIP-1 clearly fall within the subset of inducible chemokines that are believed to play a pivotal role in regulating the response of the host to invading bacterial, viral, parasite, and fungal pathogens. The most wellcharacterized aspect of MIP-1 and MIP-1 biology is their capacity to regulate the trafficking and activation state of select subgroups of inflammatory cells (including macrophages, lymphocytes, eosinophils, dendritic cells, and NK cells). The two peptides modulate other aspects of the host inflammatory response as well, including the fever response and leukocyte adhesion to the endothelium and subsequent transmigration into the tissues. While these functions clearly contribute to the ability of the host to defend itself successfully against invading pathogens, it has been hypothesized that an overly robust MIP-1 and/or MIP-1 response can, under certain circumstances, contribute to disease-related pathophysiology. This hypothesis is supported by the fact that these two molecules, either separately or together, have been implicated in a wide range of acute and chronic inflammatory conditions including bacterial sepsis, bacterial and viral meningitis, influenza virus infection, rheumatoid arthritis, asthma, multiple sclerosis, acute and chronic respiratory diseases, allograft rejection, and central nervous system disorders. An important link between MIP-1 and MIP-1 and HIV-1 infection was revealed with the discovery that CCR5 (CC chemokine receptor which binds both

MIP-1 and MIP-1 ) is utilized by macrophagetropic strains of HIV-1 as a coreceptor for entry into target cells. This discovery led to the hypothesis that the previously demonstrated antiviral actions of MIP1 and MIP-1 resulted from their interference with virus utilization of CCR5 as a coreceptor for cell entry. In addition to these critically important inflammatory and antiviral roles, both of these molecules have been shown to regulate such normal homeostatic processes as hematopoietic cell development, lymphocyte differentiation and trafficking, immune modulation, bone remodeling, and wound healing.

BACKGROUND

Discovery As has happened with other members of the chemokine family, cDNAs encoding MIP-1 and MIP-1 were cloned and recloned numerous times by several methodologies, including differential screening of cDNA libraries and subtractive hybridization (Schall, 1991; Miller and Krangel, 1992). The first cDNA clone encoding what is now referred to as MIP-1 was identified by means of a differential hybridization strategy designed to identify genes induced by PMA treatment of human tonsillar lymphocytes (Obaru et al., 1986). The cDNA clone identified by this strategy (called LD78) encoded a 92 amino acid protein containing a putative signal sequence and four internal cysteine residues. Shortly thereafter, several other groups identified cDNA clones upregulated in lymphocytes upon activation. These clones, called pAT464 and GOS-19, shared complete identity with LD78 (Zipfel et al., 1989; Blum et al., 1990). All three of these clones had been identified by expression profiling, and while the presence of a putative signal sequence in the predicted amino acid sequence for

1172 Barbara Sherry and Giovanni Franchin each suggested that the clones encoded secretory proteins, their biological function(s) were not immediately apparent, and the role that they played in the host remained a mystery. Insight into the possible function(s) of the protein encoded by the LD78 gene came from studies carried out at the same time by Wolpe et al. (1988). Using an alternative, protein-based approach rather than a cDNA sequence-based approach to identifying new gene products upregulated as a consequence of cellular activation, Wolpe and coworkers isolated two low molecular weight, heparin-binding proteins which were secreted by murine macrophages upon exposure to LPS, a classic inflammatory stimulus. As might be expected from their induction profiles, these proteins elicited an inflammatory response when injected in vivo, and possessed leukocyte chemotactic activity in vitro (Wolpe et al., 1988). Designated macrophage inflammatory protein (MIP)-1 and MIP-1 to highlight their inflammatory character (both with respect to inducibility and action), these proteins copurified through a number of chromatographic steps, but were ultimately resolved and partially sequenced by Edman degradation (Sherry et al., 1988). N-terminal sequences revealed that the two murine proteins were related to each other, and the sequence information obtained was used to generate probes for the isolation of cDNA clones encoding both proteins (Davatelis et al., 1988; Sherry et al., 1988). Both cDNA clones were predicted to encode 92 amino acid peptides containing N-terminal signal sequences. The signal peptide for each is cleaved after a serine residue to generate mature proteins of 69 amino acids. The amino acid sequence of murine MIP-1 was about 75% identical to LD78, suggesting that the two molecules were homologs (Wolpe and Cerami, 1989). In the years spanning 1988 and 1991, seven groups independently reported the isolation of closely related human cDNA clones called ACT-2, hH400, HC21, pAT744, LAG-1, G-26, and MAD-5 whose predicted products differed in sequence by only a few amino acids, suggesting that they in fact encoded a single gene product (Miller et al., 1992). Collectively, these sequences were about 75% identical to that of murine MIP-1 , suggesting that they represented its human homolog. In recent years the designations MIP-1 and MIP-1 have come to be the generally accepted designations for peptides of both human and murine origin. Comparison of the MIP-1 and MIP-1 sequences with those present in the protein databases at that time led Wolpe and Cerami (1989) to identify the existence of a large family of structurally related proteins (20±75% homology) which included MIP-1 and MIP-1 . This family now has come to be known as the chemokine family. Although many of the

sequences which belonged to this family were only predicted from cloned cDNAs, all of the family members which either had been purified from natural sources or expressed by gene cloning exhibited functional similarity (all were chemotactic for select populations of leukocytes) as well. Based upon the positioning of the first two of four cysteine residues in their amino acid sequences, chemokine family members could be subdivided into two distinct groups (CC and CXC). MIP-1 and MIP-1 were members of the CC subgroup, as were RANTES and MCP-1, and all were associated with chemoattraction of monocytes, T cells, and/or NK cells. While the murine genome contains only one copy of the MIP-1 and MIP-1 genes, several groups have reported the existence of multiple nonallelic genes for both MIP-1 and MIP-1 in humans, with the number of isoforms varying between individuals (Irving et al., 1990; Nakao et al., 1990). One of these isoforms, now referred to as MIP-1P (or LD78 ) is expressed in response to cellular activation in a pattern similar to that of MIP-1 (Nibbs et al., 1999). Although purified MIP-1P has been shown to exhibit a high degree of structural and functional similarity to MIP-1, the two can be distinguished from one another based upon receptor binding kinetics (Nibbs et al., 1999). The existence of such isoforms may explain early discrepancies among amino acid sequences predicted from independently isolated cDNA clones. As will be discussed later, the genes encoding MIP-1 and MIP-1 are closely linked in both the human and the mouse genome (Irving et al., 1990). The strong degree of similarity between these genes with respect to both sequence and chromosomal localization suggests that they arose by multiple gene duplication events from a single ancestral gene.

Alternative names MIP-1 Although MIP-1 has evolved as the primary designation for the gene product of SCYA3, this molecule has been cloned and recloned from several species by a number of different groups using a variety of techniques and rationales. As a result, it has a number of alternate designations, several of which are still used to some extent. These include LD78, pAT464, GOS19-1, SCI (stem cell inhibitor), TY-5, and L2G25B. MIP-1 is now the generally recognized name for this molecule. MIP-1P There is a second nonallelic gene (accepted gene designation SCYA3L) for MIP-1 in the human

MIP-1, MIP-1 genome (Nakao et al., 1990). The product of that gene (which shares 90% identity with MIP-1) has now been identified and functionally characterized (Nibbs et al., 1999). It has been alternatively referred to as pAT464.2, LD78 , GOS19-2, and MIP-1P. Throughout this chapter this molecule will be referred to as MIP-1P to highlight its close relationship to MIP-1. MIP-1 As in the case of MIP-1, although MIP-1 has emerged as the primary designation for the gene product of SCYA4, the molecule was cloned and recloned by a number of different groups in different species using a variety of techniques and rationales. As a result MIP-1 has a number of alternate designations, which include ACT-2 (T cell activation protein 2), pAT744, hH400, SIS , LAG-1 (lymphocyte activation gene-1), HC21, small inducible cytokine 4, G-26, and MAD-5. MIP-1 is now the generally recognized name for this molecule.

Structure MIP-1 and MIP-1 are both members of the CC subfamily of chemokines. Like other members of this subfamily, the amino acid sequences of each contain four highly conserved cysteine residues, of which the first two are adjacent to one another (Ward and Westwick, 1998). Human MIP-1 is synthesized as a 92 amino acid precursor (10,085.4 Da) which is cleaved to yield a mature protein of 70 amino acids (7787.7 Da). The intramolecular disulfide bonds bridge Cys11±Cys51 and Cys12±Cys35 (Lodi et al., 1994). Human MIP-1 is synthesized as a 92 amino acid precursor (10,211.8 Da) which is cleaved to yield mature protein of 69 amino acids (7818.7 Da). The intramolecular disulfide bonds link Cys11±Cys35 and Cys12±Cys51 (Lodi et al., 1994). Physicochemical characterization (analytical ultracentrifugation, circular dichroism, fluorescence spectroscopy, hydrophobicity analysis) have suggested that MIP-1 and MIP-1 exist as dimers or tetramers in solution (Clements et al., 1992; Patel et al., 1993; Covell et al., 1994). A dimeric structure for MIP-1 has been confirmed by nuclear magnetic resonance spectroscopy (Lodi et al., 1994; Czaplewski et al., 1999). As has been shown for all of the CC chemokines characterized to date, the dimer interface in both MIP-1 and MIP-1 is formed primarily by residues which comprise the extended amino terminus. This type of subunit arrangement results in an elongated, cylindrical dimer, which is quite different

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from the globular dimers formed by CXC chemokines (Clore and Gronenborn, 1995; Czaplewski et al., 1999). Truncation of eight or more residues at the amino terminus of MIP-1 results in a protein that is incapable of dimerization (Laurence et al., 1998). There is still some controversy as to the quarternary structure of MIP- and MIP-1 as they bind to their cognate receptors, with contradictory evidence to suggest either a monomeric or dimeric form (Laurence et al., 1998). Mutational studies with MIP-1 have identified variants that are monomeric at physiological concentrations and are equipotent to the wild-type protein regarding stem cell inhibition and induction of monocyte shape change (Graham et al., 1994). For both peptides two regions appear to be important for receptor binding, the flexible amino terminal region and a second site in the loop region that follows the two disulfides (Clark-Lewis et al., 1995). Mutational analyses indicate that, as with other CC chemokines, receptor binding and receptor activation functions are mediated by discrete sites in the molecule (Clark-Lewis et al., 1995). Both MIP-1 and MIP-1 self-associate to form high molecular weight aggregates under certain conditions (low salt, high concentration) (Graham et al., 1994). This property was fortuitous with respect to early protein purification efforts, as it caused these two proteins to elute in the void volume when fractionated by gel filtration (Wolpe et al., 1988). The aggregation of MIP-1 and MIP-1 (as well as RANTES) has been shown to be a dynamic and reversible process (Graham et al., 1994). More recent efforts to further explore the biological significance of MIP-1 aggregation have been carried out by Czaplewski et al. (1999). Using systematic mutagenesis of the MIP-1 gene and subsequent expression in yeast they generated a large set of human MIP-1 variants which fail to form aggregates as evidenced by increased mobility in nondenaturing gels and decreased apparent molecular weight by equilibrium sedimentation analysis. Studies characterizing these nonaggregating variants demonstrated that charged residues must be present at both position 26 and position 66 of MIP-1 for extensive aggregation to occur. Substitution at either of these two residues results in the formation of homogeneous dimers or tetramers. When the corresponding charged residues in human MIP-1 (Asp27 and Glu67) are replaced with uncharged glycine residues the tendency of the mutated proteins to aggregate is dramatically reduced, in a fashion similar to that seen with MIP-1 (Czaplewski et al., 1999). MIP-1 and MIP-1 mutants, while unable to form aggregates, are equipotent with respect to receptor binding and receptor-mediated biological activities. This physical attribute is likely to be

1174 Barbara Sherry and Giovanni Franchin important with respect to clinical use of either MIP1 or MIP-1 analogs, as the mutated proteins which fail to aggregate exhibit greatly improved solubility properties. Early biochemical characterization of MIP-1 and MIP-1 revealed that both proteins bound heparin with high affinity (Wolpe et al., 1988). Koopmann and Krangel (1997) have characterized a glycosoaminoglycan-binding motif in MIP-1 comprising three noncontiguous basic amino acids (Arg18, Arg26, and Arg48) which presumably mediates this activity (Koopmann and Krangel, 1997). Mutagenesis studies demonstrated that this glycosoaminoglycan-binding site is not essential for either receptor binding or signaling (Koopmann and Krangel, 1997). Similar findings have now been reported for MIP-1 (Koopman et al., 1999). It has been proposed recently (Proudfoot et al., 1999) that the glycosoaminoglycanbinding properties of these two proteins, rather than playing a role in receptor binding, facilitate their interaction with glycosoaminoglycans present on the surface of cells, increasing local chemokine concentrations by enhancing oligomerization. Such complexes have been observed to be secreted from activated T cells (Wagner et al., 1998).

Main activities and pathophysiological roles MIP-1 and MIP-1 mediate a wide range of biological activities in vitro, and the two proteins appear to have discrete roles in normal physiological processes as modulators of homeostatic processes as well as host-protective inflammatory responses. In addition, each contributes, under certain circumstances, to disease-associated pathophysiology. The main areas in which these two molecules function are cellular recruitment and trafficking, host inflammatory responses, immune regulation, hematopoiesis, and viral infection. Cellular Recruitment and Trafficking Controlled recruitment of leukocytes is a prominent feature of the host inflammatory response, and leads to the accumulation of immune cells at sites of inflammation. This is a multistep process which involves the migration of leukocytes toward the site of tissue damage, followed by attachment to endothelial cells lining the surrounding microvessels, and migration into the tissues. Among the first immune cells to arrive at the site of tissue damage are neutrophils, which initiate a rapid, nonspecific, phagocytic response. While MIP-1 and MIP-1 are not chemotactic for neutrophils in vitro, when administered

in vivo these two molecules elicit a rapid influx of neutrophils to the site of injection (Wolpe et al., 1988; Alam et al., 1994). Antibody neutralization studies have shown that in animal models (e.g. bacterial meningitis, mycobacterial infection) in which a robust accumulation of neutrophils is a characteristic feature, MIP-1 and MIP-1 play an essential role (Appelberg, 1992; Diab et al., 1999). This initial response is augmented both in magnitude and specificity by the subsequent recruitment of monocytes and specific subsets of T and B cells to the inflamed site, where they become activated to release additional host-protective inflammatory molecules. MIP-1 and MIP-1 have been shown to be potent macrophage and lymphocyte chemoattractants in vitro (Rollins, 1997; Ward and Westwick, 1998). While both proteins exert similar effects on monocytes, their effects on lymphocytes differ, with MIP-1 selectively attracting CD8‡ lymphocytes, and MIP-1 selectively attracting CD4‡ lymphocytes (Ward and Westwick, 1998). Antibody neutralization and targeted gene deletion approaches in numerous animal models of wound healing, viral infection, and inflammatory and autoimmune diseases have now confirmed the role of these two molecules as central mediators of monocyte and/or lymphocyte recruitment to inflammatory sites in the periphery, as well as in the CNS compartment (Di Pietro et al., 1998; Locati and Murphy, 1999; Xia and Hyman, 1999). MIP-1 and/or MIP-1 have also been shown to be potent chemoattractants for B cells, eosinophils, NK cells, and dendritic cells (Schall, 1994; Maghazachi and Al-Aoukaty, 1998; Dieu-Nosjean et al., 1999). In addition to temporally regulating the recruitment of inflammatory cells, MIP-1 and MIP-1 may play a role in the adhesion of recruited inflammatory cells to the endothelium, promoting the migration of specific subpopulations of leukocytes into the tissues. Both proteins have been shown to stimulate T cell adhesion to endothelial cells (Tanaka et al., 1993, 1998a; Taub et al., 1993). The actions of MIP-1 and MIP-1 are selective, with MIP-1 promoting the adhesion of CD8‡ T cells and MIP-1 promoting the adhesion of CD4‡ T cells (Taub et al., 1993). In vivo these two chemokines are thought to accumulate on endothelial surfaces via interaction with cell surface heparin sulfate proteoglycans, and to facilitate firm T cell adhesion by inducing cytoskeletal reorganization and subsequent integrin triggering in nearby T cells (Tanaka et al., 1998a). A listing of animal disease models in which a role for MIP-1 and/or MIP- in the trafficking of immune and inflammatory cells has been demonstrated by antibody neutralization or targeted gene deletion strategies can be found in Table 10, and in accompanying discussion.

MIP-1, MIP-1 Host Inflammatory Responses An organism's second concern following tissue injury (after recruiting the appropriate cells to the appropriate compartment) is to destroy any pathogenic or opportunistic organisms present in the tissues. To achieve this end, the organism must activate inflammatory cells to kill invading pathogens or invading tumors, clean up and remove debris, and remodel damaged tissues. In addition to participating in the first step of selectively attracting specific subpopulations of leukocytes to the site of inflammation, MIP1 and MIP-1 appear to participate in this second phase as well. In this regard, MIP-1 (but not MIP1 ) modulates, through autocrine mechanisms, the activation state of the macrophage. Treatment of murine macrophages with MIP-1 stimulates proinflammatory cytokine expression (TNF, IL-1), and enhances tumoricidal activity (Fahey et al., 1992). MIP-1 has also been shown to activate the respiratory burst in macrophages, and to upregulate the expression of integrins (Vaddi and Newton, 1994a; Uguccioni et al., 1995). In vivo antibody neutralization and targeted gene deletion studies in experimental animals have confirmed a critical role for MIP-1 and MIP-1 in host-protective inflammatory responses to invading pathogens (for a complete listing see Table 10). For example, a recent study demonstrated that MIP-1 responses in the CNS of mice during C. neoformans infection are protective and function to clear disseminated infection (Huffnagle and McNeil, 1999). A large number of studies have now demonstrated tissue-specific expression of MIP-1 and MIP-1 in analogous human disease states, where they presumably mediate similar host-protective responses (for a complete listing see Table 11 and Table 12). Within the framework of the host acute phase response to infection, fever is believed to be a critically important nonspecific mechanism of host defense (Kluger, 1986). In fact, in numerous animal infection models moderate fevers have been shown to decrease morbidity and increase survival rate (Kluger, 1986). Peripheral administration of MIP-1 and MIP-1 have been shown to induce a prostaglandinindependent fever in rabbits and in rats (Davatelis et al., 1989; Minano et al., 1990). In rats MIP-1 and MIP-1 have also been shown to induce a prostaglandin-independent fever when injected directly into the anterior hypothalamic-preoptic area (AH-POA) (Minano et al., 1990; Tavares and Minano, 1998). Although the widely accepted paradigm of fever is that prostaglandin E2 (PGE2) is a final central mediator which induces fever by resetting the hypothalamic thermoregulatory `set

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point' to a new higher level, a large body of work now suggests that the situation may be more complex, with a major prostaglandin-dependent component, but also a prostaglandin-independent component (Fraifeld and Kaplanski, 1998). MIP-1 and/or MIP-1 may mediate this prostaglandin-independent component in vivo. Hematopoiesis In addition to their roles in cellular recruitment and inflammatory responses, MIP-1 and MIP-1 are believed to play a role in hematopoietic cell development. The maturation of hematopoietic progenitor cells in the bone marrow is regulated through the actions of a variety of colony-stimulating factors and cytokines which govern the production and movement of stem and progenitor cells. MIP-1 and MIP-1 appear to play a regulatory role in this development process, exerting varied effects on several different progenitor cell populations (Rollins, 1997). MIP-1 has been shown to suppress the growth of immature populations of bone marrow-derived progenitor cells which are not yet committed to a specific developmental lineage (Rollins, 1997). MIP-1 was first shown to suppress the proliferation of an immature, multi-growth factor-dependent, subset of progenitor cells, CFU-spleen (CFU-S) (Graham et al., 1990). It was by following this biological activity that Graham and colleagues recloned MIP-1 as stem cell inhibitor (SCI). Later MIP-1 was shown to suppress multiple immature myeloid progenitor cell populations, including BFU-E, CFU-GM, and CFUGEMM, all of which are dependent on erythropoietin plus IL-3, GM-CSF, or steel factor (SLF) for growth (Broxmeyer et al., 1990, 1993; Keller et al., 1994). The ability of MIP-1 to suppress immature progenitor cell growth has been reproduced in vivo in mice, and more recently, it has been confirmed in patients with breast cancer undergoing a phase I clinical trial with BB-10010, an analog of MIP-1 in which a single amino acid change has been made (Broxmeyer et al., 1998). MIP-1 does not exert any of these growth suppressive activities, and in fact it has been shown to block the growth suppressive action of MIP-1 on immature bone marrow progenitors (Broxmeyer et al., 1991). The mechanism by which MIP-1 blocks the suppressive action of MIP-1 is not understood at present. The situation is quite different with respect to megakaryocyte development, where both MIP-1 and MIP-1 have been reported to inhibit growth (Gewirtz et al., 1995). It is important to note that the stem cell inhibitory activity of MIP-1 does not seem to be limited to hematopoietic tissues. Inhibition has also been reported for another mesodermal tissue,

1176 Barbara Sherry and Giovanni Franchin seminiferous epithelium, as well as tissues of ectodermal (epidermis) and endodermal (small intestine) origins (Arango et al., 1999). In sharp contrast to these growth suppressive effects on primitive progenitor cells, both MIP-1 and MIP-1 have been reported to enhance the proliferation of a population of committed granulocytemacrophage progenitors, CFU-GM, a more mature population of progenitor cells which rely on a single growth factor for expansion and which have been stimulated to proliferate in response to either GMCSF or CSF-1 (but not G-CSF) (Broxmeyer et al., 1989). In addition to modulating the development of bone marrow progenitors, MIP-1 has also been found to mobilize mature and immature myeloid progenitor cells to the blood (Lord et al., 1995). Immune Regulation Selective leukocyte migration is essential for immune surveillance of the body's tissues and for focusing immune cells to sites of antigenic challenge. Dendritic cells can act as sentinels to capture, process, and transport antigen to secondary lymphoid tissues where they then serve as potent APCs capable of stimulating T cells, and thus are believed to be critical in both initiating and modulating immune responses. The recent discovery that both MIP-1 and MIP-1 are potent dendritic cell chemoattractants suggests a role for these proteins in the initiation of immune responses via the recruitment of these potent antigen presenting cells (Dieu-Nosjean et al., 1999). In addition, it has been hypothesized that the activity of MIP-1 and MIP-1 to selectively recruit discrete subpopulations of lymphocytes may actually direct immune responses along a cell-mediated (versus humoral) immunity pathway. This hypothesis is supported by recent studies which have demonstrated that the proinflammatory TH1 subset is preferentially responsive to MIP-1 and MIP-1 chemoattraction (Siveke and Hamann, 1998). The preferential response of TH1 versus TH2 subsets to MIP-1 and MIP-1 can be explained by the recent observation that these two cell types express different chemokine receptor profiles, with TH1 (but not TH2) cells expressing high levels of CCR5, a CC chemokine receptor which binds MIP-1 and MIP-1 (Ward and Westwick, 1998). Interestingly, recent reports show a secretion of MIP-1 and MIP-1 by TH1 cells, but not by TH2 cells in humans (Schrum et al., 1996, Pearlman et al., 1997). Taken together these findings indicate the existence of a positive feedback loop that links early secretion of MIP-1 and MIP-1 by activated TH1 cells at an inflamed site with the recruitment of additional TH1 cells which, upon

subsequent activation, could secrete even more MIP1 and MIP-1 . The activity of MIP-1 to influence TH1 responses may extend beyond selective recruitment, as evidenced by the proven activity of this molecule to drive TH0 cells to differentiate to TH1 cells (Karpus and Kennedy, 1997). MIP-1 is also believed to be an important effector in innate immune responses via its ability to modulate the migratory pathways and activation state of NK cells (Maghazachi and Al-Aoukaty, 1998). Viral Infection The generation of MIP-1 knockout mice by targeted gene deletion led to the discovery that MIP-1 plays an important role in host antiviral responses and associated pathologies (Cook, 1996). This role is highlighted by the observation that infection of MIP1 knockout mice with influenza virus results in a substantially reduced recruitment of CD8‡ T cells into the infected lung as compared with that seen in wild-type mice (Cook et al., 1995). This failure to recruit CD8‡ T cells to the lung leads to a significant reduction in the histologic degree of infection-associated pneumonitis and a pronounced delay in resolution of the viral infection. Another example of the importance of endogenously produced MIP-1 in host antiviral inflammatory responses was revealed when MIP-1 knockout mice were infected with Coxsackie virus. Unlike their wild-type counterparts, MIP-1 knockout mice failed to develop the profound myocarditis normally associated with the disease (Cook et al., 1995). In addition to participating in the host inflammatory response to viral infection, two further seminal discoveries were made in the mid-1990s which revealed an important role relating to MIP-1 and MIP1 , as well as several other chemokine family members (RANTES, SDF-1), in the establishment and progression of HIV infection (Alkhatib et al., 1996). Firstly, MIP-1 and MIP-1, along with RANTES, were found to inhibit infection by macrophage-tropic strains of HIV-1 (Cocchi et al., 1995). Secondly, macrophage-tropic strains of HIV-1 were found to utilize the CC chemokine receptor CCR5 as a coreceptor for viral entry into susceptible target cells (Alkhatib et al., 1996; Dragic et al., 1996; Feng et al., 1996). This second discovery led to the hypothesis that the antiviral actions of MIP-1 and MIP-1 resulted from their interference with virus utilization of CCR5 (MIP-1/MIP-1 receptor) as a coreceptor for cell entry by the virus. The functional importance of CCR5 in HIV infection has now been confirmed by the discovery that individuals homozygous for a 32 bp deletion in CCR5 have a markedly reduced

MIP-1, MIP-1 susceptibility to HIV infection (Liu et al., 1996). The capacity of CC chemokines to suppress infection of CD4‡ T cells by primary HIV-1 isolates has resulted in targeting chemokine receptors as a therapeutic strategy in the effort to combat the AIDS epidemic (Proudfoot et al., 1999). However, the role of endogenously produced CC chemokines, including MIP-1 and MIP-1 , in infected individuals is not clear, as serum levels of these peptides were found to be even higher in patients with AIDS as compared with nonprogressors (McKenzie et al., 1996; Zanussi et al., 1996). Nevertheless, those patients with the highest levels of MIP-1, MIP-1 , and RANTES show more delayed disease progression (Gallo et al., 1996). Dendritic cells are an important target for HIV, and although it remains somewhat controversial, several studies have shown that dendritic cells maturing from CD4‡ stem cells can be infected with both macrophage-tropic and T-tropic viruses (Wang et al., 1999). In one study, MIP-1 and MIP-1 suppressed the infection of M-tropic viruses in maturing dendritic cells, but enhanced the infection of T-tropic viruses (Wang et al., 1999). These results raise the possibility that elevated CC chemokine levels as seen in some patients or as a result of artificial intervention may exert a selective pressure on the virus and contribute to a change in viral tropism.

GENE AND GENE REGULATION

Accession numbers See Table 1.

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Chromosome location In humans, the MIP-1 gene (designation SCYA3) and the MIP-1 gene (designation SCYA4) have been shown to map to chromosome 17 (loci q11-21 and q21-23, respectively) by fluorescence in situ hybridization (Irving et al., 1990). The genes encoding other CC chemokines, including human I-309, MCP-1, and RANTES, are clustered in this same region (Miller and Krangel, 1992). The murine MIP-1 gene (designation scya3) and the murine MIP-1 gene (designation scya4) are located on mouse chromosome 11 where they are clustered with other genes encoding murine CC chemokines (Wilson et al., 1990). The human and murine MIP-1 and MIP-1 genes, like other CC chemokine genes, are arranged in a three exon/two intron configuration (See Figure 1) (Schall, 1991; Widmer et al., 1993). Each of the human genes is present in an additional nonallelic copy as part of an apparent amplification unit found in the genome of many individuals (Irving et al., 1990). MIP-1P (originally identified as pAT464.2, LD78 ), a nonallelic copy of the MIP-1 gene, is expressed and encodes a protein highly related to MIP-1, varying in 5 of 92 amino acids.

Relevant linkages On human chromosome 17, the genes encoding MIP1 and MIP-1 are separated by a distance of only 14 kb, and are organized in a head-to-head orientation allowing for the possibility that they may share certain regulatory elements (Irving et al., 1990). The two genes are closely linked to one another as

Table 1 MIP-1 and MIP-1 accession IDs cDNA accession nos. (GenBank)

Genomic accession nos. (human: GBI/GenBank, murine: MGI/MGD)

Human

M23452, M25315, X03754, D00044, D63785, AF043339

120368, D90144, M23178, D90144, AB012113, AF082214

Mouse

M23447, X12531, X53372, J04491, M73061, M19382, M36678

MGI-98260, MGD-MRK-12241, MGD-MRK-14334

Human

X16166, J04130, M23502, M25316, M57503, X53683, M69203

GDB:120369, M69203

Mouse

M23503, M35590, X62502, S61348, X52502

MGI:98261, MGC-MRK-12242, MGD-MRK-14335

MIP-1

MIP-1

1178 Barbara Sherry and Giovanni Franchin Figure 1 Schematic comparison of human MIP1, MIP-1P, and MIP-1 genomic organization (adapted from Schall, 1991). Intron/exon diagrams representing the genes for MIP-1, MIP1P, and MIP-1 , having all been mapped to chromosome 17q11.2-q21. Boxes denote exons, with open spaces representing untranslated regions, hatched areas representing signal peptide coding nucleotides, and filled areas representing mature protein coding nucleotides. Numbers above boxes refer to amino acids encoded by that exon. Lines represent introns, with numbers in parentheses representing the number of nucleotides in that intron.

MIP-1 DNA-binding studies (Grove and Plumb, 1993) led to the identification of five major nuclear protein-binding sites in the proximal promoter of the MIP-1 gene which bind NF-IL6 (C/EPB), NFB, and/or c-Ets family members in macrophages. MIP-1 is known to be differentially regulated in monocytes and T cells. Nomiyama et al. (1993) identified a domain in the MIP-1 promoter which was responsible for some of these differences, and further showed that the domain contained a DNA-binding site (the ICK site ÿ107 to ÿ94) for four related transcription factors, ICK1A, -1B, -1C, and -1D. Binding of these factors to the promotor was shown to differentially modulate MIP1 transcription. More recently, Ritter et al. (1995) identified a family of hematopoietic transcription factors, the MIP-1 nuclear protein (MNP) family, whose expression is crucial for the induction of MIP1 transcription during cellular activation in monocytes, lymphocytes, and transformed B cells. Separate MNP family members are involved in regulating MIP-1 expression in monocytes, transformed B cells, and differentiated macrophages (Sharma et al., 1998). Xia et al. (1997) have demonstrated by RNase protection analysis that RelB negatively regulates MIP-1 gene induction in fibroblasts, a nonhematopoietic cell type.

MIP-1 determined by population linkage disequilibrium studies (Irving et al., 1990). They are also closely linked to other CC chemokine genes as determined by the same technique (Schall, 1991). Although no linkages to particular disease states have yet been documented, the region on chromosome 17 at q11q23 where the MIP-1 and MIP-1 genes are found has been implicated in von Recklinghausen neurofibromatosis (NF1) and acute promyelocytic leukemia (AML-M3) (Irving et al., 1990).

Regulatory sites and corresponding transcription factors While the MIP-1 and MIP-1 genes are coordinately regulated in many cells and tissues, characterization of the human and murine promoters of both molecules has revealed considerable heterogeneity, and therefore the regulatory sites, and corresponding transcription factors, which control expression of these two genes will be discussed separately.

Analysis of the 50 regulatory region of the human MIP-1 gene revealed three consensus-binding sites for the nuclear factor PU.1, and three potential glucocorticoid response elements (GREs) (Ziegler et al., 1991). Although the presence of three potential GREs within the 50 regulatory region of the MIP-1 gene suggested that corticosteroids might regulate MIP-1 gene expression, in vitro studies in human moncytes indicate that LPS-induced MIP-1 expression is unresponsive to dexamethasone treatment. Also present in the 50 regulatory region was an LPSresponsive element located within 455 bp 50 to the start of transcription, and a sequence (50 GAAATTCCAC-30 ) starting at position -84 that very closely resembled the consensus sequence for a motif known as the lymphokine box which is also found upstream of the human MIP-1 gene (Ziegler et al., 1991). The relevance of this sequence is unknown. Surprisingly, no consensus AP-1 or NFB binding sites were found in the 50 regulatory region. Proffitt et al. (1995) identified an essential cisregulatory element in the proximal promoter of the murine MIP-1 gene that is essential for cell-specific

MIP-1, MIP-1 and inducible transcription in functional transfection studies in murine macrophages. Mutational analysis implicated this ATF/CREB site in LPS inducibility (Proffitt et al., 1995).

Cells and tissues that express the gene In most cells and tissues the MIP-1 and the MIP-1 genes are not constitutively expressed, but rather are upregulated as a consequence of cellular activation either by cytokine stimulation, intracellular infection, or exposure to disease-specific determinants (Ward and Westwick, 1998). There are several exceptions to this rule. In humans, constitutive expression of MIP1 has been detected within the bone marrow compartment (Kukita et al., 1997). The expression of MIP-1 was localized to eosinophilic myelocytes by in situ hybridization. Constitutive expression of MIP1 was also observed in osteoblasts at sites of bone remodeling, and osteoclasts were frequently observed in the vicinity of the MIP-1-expressing osteoblasts (Kukita et al., 1997). Parkinson et al. (1993) reported constitutive expression of MIP-1 in mouse skin, localized to epidermal Langerhans cells. Mohamadzadeh et al. (1997) reported constitutive expression of MIP-1 in dendritic cells from dermis, spleen, and lymph nodes of mice. In rats, MIP-1 has been detected in tissues from both primitive and advanced spermatogenic cells (Hakovirta et al., 1994). Also, a number of tumor cells have been shown to constitutively express MIP-1 and/or MIP-1 in situ (e.g. acute T lymphocytic leukemia cells) (Yamamura et al., 1989). While the latter observations suggest a pro-tumor role for constitutively expressed chemokines, other studies report that tumor infiltrating

1179

lymphocytes (TILs) which invade solid tumors also constitutively express these chemokines, suggesting a potential antitumor function (Tanaka et al., 1998c). The activation-induced expression profiles of the two genes in isolated cell populations in vitro and in organs/tissues in vivo can be found in Table 2 and Table 3, and in the accompanying discussion. Tissuespecific expression of the MIP-1 and/or the MIP-1 genes has now been demonstrated in a large number of experimental animal disease models. A listing of experimental animal disease models in which MIP-1 and/or MIP-1 expression is upregulated in a cell- or tissue-specific manner can be found in Table 8 and Table 9. In humans, the MIP-1 and/or the MIP-1 genes are also upregulated in a number of disease states. A complete listing of human disease states in which MIP-1 and/or MIP-1 gene expression is upregulated in a tissue-specific manner can be found in Table 11 and Table 12.

PROTEIN

Accession numbers Human: MIP-1: P10147, P16619 MIP-1 : P13236 Mouse: MIP-1: P10855, P14096 MIP-1 : P14097

Sequence See Figure 2.

Figure 2 Protein sequences of human MIP-1, MIP-1P, and MIP-1 ; signal peptides are underlined.

1180 Barbara Sherry and Giovanni Franchin

Description of protein MIP-1 and MIP-1 are both members of the CC subfamily of chemokines. Like other members of this subfamily, the amino acid sequences of each contain four highly conserved cysteine residues, of which the first two are adjacent to one another (Ward and Westwick, 1998). The structure and physical properties of the MIP-1 and MIP-1 proteins have been described in detail in the section on Structure.

Discussion of crystal structure Although the X-ray crystal structures of MIP-1 and MIP-1 have not yet been reported, the threedimensional NMR structure of human MIP-1 has been determined (Lodi et al., 1994). The secondary structure of monomeric MIP-1 comprises a triplestranded antiparallel sheet arranged in a Greek key motif and a C-terminal  helix (Lodi et al., 1994). This is very similar to the secondary structure of other chemokine family members (Clore and Gronenborn, 1995; Skelton et al., 1995). While the NMR structure of human MIP-1 has not been determined experimentally, its three-dimensional structure has been modeled using known chemokine structures as templates (McKie and Douglas, 1994). Recently, the three-dimensional NMR structure of BB-10010 (an analog of MIP-1 containing a single amino acid mutation which blocks its ability to aggregate) has been reported (Czaplewski et al., 1999). The structure of BB-10010 obtained by NMR spectroscopy is consistent with the three-dimensional structure predicted for MIP-1. The marked structural similarity

between MIP-1 and MIP-1 can be seen in Figure 3, which provides ribbon representations of the peptide backbones of the MIP-1 and MIP-1 monomers. Figure 4 provides a comparable view of the MIP-1 dimer. By comparing the solution structure of MIP-1 with that of another CC chemokine, RANTES, it was determined that the highest degree of structural variability between these two closely related CC chemokines is found in the N-terminal region (Skelton et al., 1995). The contribution of the length of the N-terminus to the oligomerization state has been examined for MIP-1 (Laurence et al., 1998). The results show that with a truncation of up to five residues, a dimeric form is favored at millimolar concentrations, while a truncation of six and more residues results in decreased dimer affinity. After truncation of eight residues, MIP-1 exists solely as a folded monomer (Laurence et al., 1998). These results suggest a general correlation between the length of the N-terminus and the oligomerization tendency of chemokines. For MIP-1 , it was shown that physiological salt concentrations drastically shift the monomer±dimer equilibrium for both wild-type and mutant proteins, favoring the dimeric form (Laurence et al., 1998).

Important homologies Amino acid sequence and hydrophilicity comparisons identified MIP-1 and MIP- as founding members of the chemokine family (Wolpe and Cerami, 1989). The adjacent positioning of the first two of four conserved cysteines within both of their primary

Figure 3 Schematic representation of the structural three-dimensional model (ribbon) of human MIP-1 and MIP-1 as analyzed by SwissModel version 3.5 (Peitsch, 1996; Guex and Peitsch, 1997). The N-terminal end is colored blue and residues of cysteine and proline are labeled. (Full colour figure can be viewed online.)

MIP-1, MIP-1

Figure 4 Schematic representation of the structural three-dimensional model of human MIP-1 dimer obtained from the Swiss-3D image collection (Peitsch et al., 1995). The illustration shows each monomer in a different color (green and blue) and the disulfide bridges are depicted in yellow. (Full colour figure can be viewed online.)

sequences suggested the inclusion of both proteins as members of a CC subgroup of the chemokine family (Wolpe and Cerami, 1989; Baggiolini et al., 1997). Sequence homology comparisons, taking into consideration the large number of newly discovered chemokine family members, reveals that the CC subgroup can be further divided into two, or possibly three, loosely defined clusters (Figure 5). At the protein level, MIP-1 shares the highest degree of sequence homology with MIP-1P, MIP-4, HCC-2, MIP-1 , and MPIF1 (94%, 59%, 56%, 55%, and 51% sequence identity with MIP-1, respectively) (Patel et al., 1997; Pardigol et al., 1998; Guan et al., 1999). At the protein level, MIP-1 shares the highest degree of sequence homology with MIP-1, MIP-1P, RANTES, MIP-4, HCC-1, and MPIF1 (55%, 58%, 51%, 43%, 43%, and < 40% sequence identity with MIP-1 , respectively) (homologies determined using BLASTP 2.0.9 program) (Altschul et al., 1997). Although all the closely related proteins within this cluster display considerable sequence homology, and exert overlapping biological activities due in part to shared utilization of receptors (O'Garra et al., 1998; Kim and Broxmeyer, 1999), MIP-1 and MIP-1 are the two proteins which share the highest degree of homology with respect to regulation of expression. Neither is expressed in the absence of activation, and both are upregulated in

1181

Figure 5 Dendrogram representing the relationship of amino acid sequences of human MIP-1, MIP-1P, and MIP-1 (bold type in figure) as compared with other members of the CC chemokine family. Protein sequences were grouped in clusters by examining sequence distances between all pairs using the CLUSTAL V method (MegAlign 3.03c version) (Higgins and Sharp, 1989). The parameters for Ktuple, gap penalty, window, and diagonals saved were set at 1, 3, 10, and 5 respectively. Phylogenies are rooted assuming a biological clock. The length of each pair of branches represents the distance between sequence pairs.

response to TH1 cytokines. MIP-4, while also an inducible protein, is upregulated in response to TH2 cytokines (Kodelja et al., 1998). The remaining proteins with closest homology (HCC-2, MPIF1, RANTES) are expressed constitutively in specific tissues (Schall, 1991; Kim and Broxmeyer, 1999). For both MIP-1 and MIP-1 the interspecies homologies are > 70%. A dendrogram illustrating interspecies relationships of MIP-1 and MIP-1 can be found in Figure 6, and a direct comparison of the sequences of all MIP-1 and MIP-1 species cloned to date can be found in Figure 7.

1182 Barbara Sherry and Giovanni Franchin Figure 6 Dendrogram representing the amino acid sequence relationships of MIP-1, MIP-1 , and RANTES among different species (human sequences appear in bold). Protein sequences were grouped in clusters by examining sequence distances between all pairs using the CLUSTAL V method (MegAlign 3.03c version) (Higgins and Sharp, 1989). The parameters for Ktuple, gap penalty, window, and diagonals saved were set at 1, 3, 10, and 5 respectively. Phylogenies are rooted assuming a biological clock. The length of each pair of branches represents the distance between sequence pairs.

absence of endogenous or exogenous stimulation. While not expressed constitutively, MIP-1 protein is rapidly synthesized and secreted by a wide range of cultured cells and by a wide range of cells/tissues in vivo in response to a broad range of activation stimuli (Baggiolini et al., 1994; Ward and Westwick, 1998). The cell types (together with induction profiles) in which MIP-1 expression has been demonstrated in vitro are listed in Table 2. In mice and rats, MIP-1 expression is markedly upregulated in blood leukocytes and in the lung in response to LPS, staphylococcal enterotoxin B (SEB), TNF, and IL-1 challenge (Standiford et al., 1995; Tessier et al., 1997; Neumann et al., 1998). MIP-1 is also upregulated in organs/tissues in a large number of animal disease models (see Table 8 for listing). Similarly to MIP-1, MIP-1 is not routinely secreted by cultured cells, nor by cells/tissues in vivo, in the absence of endogenous or exogenous stimulation. However, the protein is rapidly synthesized and secreted by a wide range of cultured cells in vitro and by a wide range of cells/tissues in vivo in response to a broad range of activation stimuli. The cell types (together with induction profiles) in which MIP-1 expression has been demonstrated in cultured cells are listed in Table 3. MIP-1 is also upregulated in organs/tissues in a large number of animal disease models as well (see Table 9 for listing).

Posttranslational modifications There are no known posttranslational modifications of either MIP-1 or MIP-1 . Analysis of the primary amino acid sequence of the two human proteins does not reveal any potential N-linked glycosylation sites. MIP-1 and MIP-1 both have two potential O-linked glycosylation sites (Thr29 and Ser36 in MIP-1; Ser23 and Ser28 in MIP-1 ), but whether these residues are glycosylated in the native proteins is not known. In murine MIP-1 there is a potential N-linked glycosylation site (Asn-Pro-Ser) starting at position 53, but the presence of a proline residue in the middle position strongly argues against its use.

CELLULAR SOURCES AND TISSUE EXPRESSION

Cellular sources that produce Except where noted above, MIP-1 is not detectable in cultured cells or in cells/tissues in vivo in the

Eliciting and inhibitory stimuli, including exogenous and endogenous modulators Stimuli, including exogenous and endogenous modulators, known to elicit the production of MIP-1 and/or MIP-1 in specific cell types are listed in Table 2 (for MIP-1) and Table 3 (for MIP-1 ). The immunomodulatory cytokines and anti-inflammatory agents that negatively regulate activation-induced MIP-1 and/or MIP-1 production in cultured cells are catalogued in Table 4. Several of the inhibitory molecules shown to negatively regulate MIP-1 peptide expression in vitro have now been shown to act similarly in vivo. In several models of acute inflammation (e.g. zymosan-induced peritonitis, LPSinduced sepsis) MIP-1 responses are negatively regulated by IL-10 (Ajuebor et al., 1999). IL-10 is also an endogenous negative regulator of MIP-1 expression in type II collagen-induced arthritis (Kasama et al., 1995b). MIP-1 expression in the lungs of rats challenged with LPS is inhibited by

MIP-1, MIP-1

1183

Figure 7 Comparison of the primary amino acid sequences of interspecies MIP-1, MIP-1 , and RANTES. The protein sequences were aligned using the MegAlign program version 3.03c. Alignment parameters and protein sequence accession numbers used were the same as used for construction of phylogeny tree. Boxes shaded in blue represent amino acids that match the consensus exactly. (Full colour figure can be viewed online.)

pretreatment with either dexamethasone or ibuprofen (Qiu et al., 1997).

RECEPTOR UTILIZATION The receptors for MIP-1 and MIP-1 belong to a family of structurally related, seven-transmembranespanning proteins that are coupled to heterotrimeric guanine nucleotide-binding (G) proteins (Kelvin et al., 1993). While a subset of receptors are shared by both MIP-1 and MIP-1 (CCR5, D6/CCR9), there are receptors which bind one, but not the other (CCR1 binds MIP-1, but not MIP-1 ). This may help to explain, at least in part, why these molecules have overlapping, but not identical, bioactivity profiles. Each of the known receptors for MIP-1 and MIP-1 is the subject of separate chapters in this database, and therefore they will only be discussed briefly in this section.

MIP-1 The receptors utilized by MIP-1 to mediate its biological effects are listed in Table 5, along with their corresponding expression profiles, ligand-binding affinities, and agonists. The two major MIP-1-binding proteins characterized to date are CCR1 and CCR5, both of which are expressed on a wide range of cell types (Devalaraja and Richmond, 1999). CCR4 and D6/CCR9 have also been reported to bind MIP-1, but whether such interactions are physiologically relevant in vivo is not clear at present (Hoogewerf et al., 1996; Nibbs et al., 1997). It is important to note that MIP-1 is not a ligand for the Duffy antigen receptor (DARC), a promiscuous chemokine receptor which has been shown to bind many CC and CXC chemokines (Hadley and Peiper, 1997). Studies with CCR1 knockout mice, (Broxmeyer et al., 1999a) demonstrated that the growth-enhancing effects of MIP-1

1184 Barbara Sherry and Giovanni Franchin Table 2 Cell types in which MIP-1 expression has been demonstrated in culture Cellular sources

Ca

Ia

Eliciting stimuli

References

+

LPS

Wolpe et al., 1988

ECM components

McKee et al., 1996

CD40±CD40L engagement

Kornbluth et al., 1998

LPS ‡ IFN

Bug et al., 1998

Mycoplasmal lipopeptide (MALP-2)

Deiters and Muhlradt, 1999

TSST-1, enterotoxin B(SEB)

Krakauer, 1999

Primary cells Monocytes/macrophages

Alveolar macrophages

+

Dendritic cells

+

T lymphocytes

+

Influenza virus infection

Bussfeld et al., 1998

Listeria monocytogenes infection

Flesch et al., 1998

Borrelia burgdorferi infection

Sprenger et al., 1997

Mycobacterium tuberculosis infection

Sadek et al., 1998

HIV-1 infection

Schmidtmayerova et al., 1996

IgE crosslinking

Gosset et al., 1999

TNF, adherence to plastic

Driscoll et al., 1995

CD40±CD40L

McDyer et al., 1999

LPS, TNF

Sallusto et al., 1999

CD3 ligation, PHA, Con A, PMA

Ward and Westwick, 1998 Oppenheim et al., 1991

CD3 ligation ‡ CD28 costimulation

Herold et al., 1997

B lymphocytes

+

Antigen receptor triggering, SAC

Krzysiek et al., 1999

NK cells

+

IL-15, IL-12 ‡ (IL-15, TNF, or IL-1 )

Bluman et al., 1996

CTLs

+

Antigen-specific activation

Wagner et al., 1998

Neutrophils

+

LPS, LPS ‡ IFN , A23187

Kasama et al., 1995a

Infection with S. typhimurium, P. aeruginosa, S. aureus

Hachicha et al., 1998

EBV, TNF, GM-CSF

McColl et al., 1997

Eosinophils

+

RSV infection,

Olszewska-Pazdrak et al., 1998

Calcium ionophore-A23187

Li et al., 1996

Basophils

+

IL-3, anti-IgE, IL-3 ‡ anti-IgE

Li et al., 1996

Mast cells

+

IgE receptor-dependent Ag challenge

Yano et al., 1997

Con A, PMA ‡ ionomycin

Burd et al., 1989

Platelets

+

Upon storage

Klinger et al., 1995

Endothelial cells

+

IL-1

Hesselgesser and Horuk, 1999

Epithelial cells

+

RSV infection, M. tuberculosis infection

Olszewska-Pazdrak et al., 1998

Glycated serum albumin

Bian et al., 1996

Constitutively expressed

Matsue et al., 1992

Keratinocytes

Langerhans cells

+ +

HSV infection

Mikloska et al., 1998

Fibroblasts

+

IL-1, TNF, LPSIFN ‡ IL-1

Bug et al., 1998

Mesangial cells

+

TNF ‡ IFN

Schwarz et al., 1997

Microglial cells

+

LPS, TNF, IL-1

McManus et al., 1998

MIP-1, MIP-1

1185

Table 2 (Continued ) Ca

Cellular sources

Astrocytes

Ia

Eliciting stimuli

References

-amyloid(25±35)

Meda et al., 1999

+

IFN , TNF, LPS

Guo et al., 1998

+

LPS, PMA

Ishii et al., 1998

Constitutively expressed

Yamamura et al., 1989

Tumor cells Astrocytoma cells HUT102/MT-2, MJ, ATL

+

a

`C' in title line refers to constitutive production by indicated cell type, while `I' refers to cell type in which MIP-1 is only expressed in response to stimulus noted in adjacent column. PHA, phytohemagglutinin; PMA, phorbol myristate acetate; SAC, Staphylococcus aureus Cowan I.

Table 3 Cell types in which MIP-1 expression has been demonstrated in culture Cellular sources

Ca

Ia

Eliciting stimuli

References

‡

LPS, IL-7

Ziegler et al., 1991

CD40±CD40L engagement

Kornbluth et al., 1998

ECM, hyaluronan fragments

Horton et al., 1998

TSST-1, enterotoxin B (SEB)

Krakauer, 1999

Mycobacterial lipoarabinomannan

Juffermans et al., 1999

Listeria monocytogenes infection

Flesch et al., 1998

HIV-1 infection

Schmidtmayerova et al., 1996

Primary cells Monocytes/macrophages

Alveolar macrophages

‡

TNF, adherence to plastic

Driscoll et al., 1995

Dendritic cells

‡

CD40±CD40L engagement

McDyer et al., 1999

LPS, TNF

Sallusto et al., 1999

T lymphocytes

‡

CD3 ligation, PHA, Con A, PMA

Ward and Westwick, 1998

CD3 ligation ‡ CD28 costimulation

Herold et al., 1997

B cell antigen receptor triggering, SAC

Krzysiek et al., 1999

B lymphocytes

‡

NK cells

‡

IL-15, (IL-12 ‡ IL-15), (IL-18 ‡ IL-12)

Bluman et al., 1996

CTLs

‡

Antigen-specific activation

Wagner et al., 1998

Neutrophils

‡

LPS, LPS ‡ IFN ,

Kasama et al., 1995

Mast cells

‡

IgE ‡ Ag, Con A, PMA ‡ ionomycin

Burd et al., 1989

Keratinocytes

‡

HSV infection

Mikloska et al., 1998

Fibroblasts

‡

LPS, IL-1

Xia et al., 1997

Microglial cells

‡

LPS, TNF, IL-1

McManus et al., 1998

Astrocytes

‡

LPS, TNF, IFN

Guo et al., 1998

‡

LPS, PMA

Ishii et al., 1998

‡

Constitutively expressed

Yamamura et al., 1989

Tumor cells Astrocytoma cells HUT102/MT-2, MJ

‡

a `C' in title line refers to constitutive production by indicated cell type, while `I' refers to cell type in which MIP-1 expression is only expressed in response to stimulus noted in adjacent column. PHA, phytohemagglutinin; PMA, phorbol myristate acetate; SAC, Staphylococcus aureus Cowan I.

1186 Barbara Sherry and Giovanni Franchin

Table 4 Inhibitors of MIP-1 and/or MIP-1 mRNA expression Cell type

Inhibitory molecules

Effects on MIP-1 and/or MIP-1 expression

References

Macrophages

IL-10, IL-4, IFN , TGF

#LPS-induced MIP-1 and MIP-1

Kopydlowski et al., 1999

Dexamethasone

#LPS-induced MIP-1 and MIP-1

Baggiolini et al., 1994

Pentoxyfilline

#LPS-induced MIP-1 and MIP-1

Krakauer, 1999

NG-monomethyl-L-arginine

#LPS-induced MIP-1 and MIP-1

Muhl and Dinarello, 1997

IL-1 receptor antagonist protein

#LPS-induced MIP-1 and MIP-1

Lukacs et al., 1993a

Roliplam

#LPS-induced MIP-1 and MIP-1

Kimata et al., 1998

Ibuprofen

#LPS-induced MIP-1 and MIP-1

Qui et al., 1997

Cyclosporin

#LPS-induced MIP-1 and MIP-1

Oppenheim et al., 1991

N-Acetylcysteine, antioxidants, dimethylsulfoxide

#LPS-induced MIP-1

Shi et al., 1998

IL-10, IL-4, IFN , TGF , dexamethasonea

#LPS-induced MIP-1 and MIP-1

Sherry et al., 1998; Kopydlowski et al., 1999 Baggiolini et al., 1994

Adenosine and ligands for adenosine receptor subtypes (A1, A2, A3)

#LPS-induced MIP-1

Szabo et al., 1998

Astrocyte/ microglial cells

Prostaglandins

#LPS-induced MIP-1 and MIP-1

Janabi et al., 1999

IL-10, TGF

#Cytokine-induced MIP-1 and MIP-1

Guo et al., 1998

Neutrophils

IL-4, IL-10

#LPS-induced MIP-1 and MIP-1

Kasama et al., 1995a

IFN

#Early LPS-induced chemokines

Kasama et al., 1995b

"LPS-induced chemokines in long-term cultures The effects summarized above were observed in human cells except where indicated (amurine).

on mature myeloid progenitor cells, but not its growthsuppressive effects on immature progenitors, are mediated through CCR1. In this same investigation, CCR1 was identified as the receptor responsible for MIP-1-mediated G-CSF-induced myeloid progenitor cell mobilization. Other studies, again using CCR1 knockout mice, identified CCR1 as the receptor mediating MIP-1-induced calcium mobilization in neutrophils (Zhang et al., 1999). Recent studies conducted with human MIP-1 and human MIP-1 (not a ligand for CCR1) chimeric proteins and mutants have revealed that two amino acids (Lys37 and Leu43) are important in the binding and signaling of MIP-1 through CCR1 (Crisman et al., 1999). Further mutational analysis revealed that the three charged amino acids at the C-terminus of human MIP-1 (amino acids 61, 65, 67) are not critical for its binding to CCR1 (Crisman et al., 1999). Mutagenesis studies (Maghazachi, 1999) demonstrated that MIP-1 binds the extracellular loops, and not the N-terminal segment, of CCR1.

MIP-1 also binds and signals through CCR5 which, like CCR1, is expressed on a wide range of host cells (Devalaraja and Richmond, 1999). A key region of CCR5 involved in its specific interaction with MIP-1, and subsequent activation, lies within the second extracellular loop and perhaps the adjacent transmembrane segments (Samson et al., 1997). MIP-1 has also been shown to bind to the third extracellular loop of CCR5 (Maghazachi, 1999), although the relevance of this interaction to biological activity has yet to be determined. Depending on the cell type and which receptor it has bound to, MIP-1 mediates its biological effects by selectively activating G proteins: Go, Gs, and Gz (Maghazachi, 1999), leading to the activation of intracellular effectors. It has also been shown to stimulate tyrosine phosphorylation of Pyk-1, STAT1, and STAT3 (Davis et al., 1997; Wong and Fish, 1998). A more thorough discussion of MIP-1-mediated signaling can be found in chapters reviewing CCR1 and CCR5 biology.

MIP-1, MIP-1

1187

Table 5 Human MIP-1 receptors Receptor

RNA

Kd (nM)a

Ligands

IC50 (nM)a

Agonist rank order

Selected references

CCR1

M, LT, N, B, E

10 (10) (5)

MIP-1

10 (1)

MIP-1 ˆ MCP-3 > RANTES  MIP-1 ˆ MCP-1

Sarau et al., 1997; Tsou et al., 1998

0.6 (15) (7.6)

RANTES

15 (30)

0.7 (8)

MCP-3

8 (10)

75

MIP-1

75

MDC > TARC

Imai et al., 1998

RANTES ˆ MIP-1 MIP-1 > RANTES ˆ MIP1 Kd MIP-1 1.6 nM

Wu et al., 1997

HCC-4 0.74

MPIF1 Lkn-1

CCR4

LT (memory) skin 71% and gut 7%, M

0.18

MDC (STCP-1) TARC

14

MIP-1

15

9

RANTES

9

MCP-1 CCR5

M, LT

1.56 D6

Hematopoietic tissue

MIP-1

7.4 (3)

MIP-1

7.4 (10)

RANTES

6.9 (30)

64

MIP-1

1.7

MIP-1

3.6

RANTES

16.5

MCP-1

0.76

MCP-2

1.2

MCP-3

5.9

MCP-4

46

Eotaxin

Nibbs et al., 1997

M, macrophage; N, neutrophil; LT, T lymphocyte; B, B cell; Fb, fibroblast; E, eosinophil. a Values in parentheses indicate different results reported by different authors.

MIP-1 The receptors that mediate the biological effects of MIP-1 are listed in Table 6, along with their corresponding expression profiles, ligand-binding affinities, and agonists. At present, CCR5 is generally accepted to be the major MIP-1 -binding protein on cells. Two other CC chemokine receptors, D6/CCR9 and CCR8, have recently been reported to bind MIP-1 (Bonini et al.,

1997; Bernardini et al., 1998), but whether these interactions are physiologically relevant in vivo is unknown, and the MIP-1 /CCR8 interaction remains somewhat controversial (Tiffany et al., 1997). Unlike many other chemokines, MIP-1 is not a ligand for the Duffy antigen receptor (DARC) (Hadley and Peiper, 1997). MIP-1 has been shown by mutational analysis to bind to the third extracellular loop of CCR5 (Maghazachi, 1999). Mutational analysis has

1188 Barbara Sherry and Giovanni Franchin

Table 6 Human MIP-1 receptors Receptor

RNA

CCR5

M, LT

kD (nM)

1.56 CCR8

Lymphoid organs, Thymus, low in spleen

Ligands

IC50 (nM)a

Agonist rank order

Selected references

MIP-1

7.4 (3)

RANTES ˆ MIP-1 MIP-1 > RANTES ˆ MIP1 Kd MIP-1 1.6 nM

Wu et al., 1997

MIP-1

7.4 (10)

RANTES

6.9 (30)

I-309

(2)

Tiffany et al., 1997; Bernadini et al., 1998

TARC MIP-1 D6

Hemopoietic tissue

64

MIP-1

1.7

MIP-1

3.6

RANTES

16.5

MCP-1

0.76

MCP-2

1.2

MCP-3

5.9

MCP-4

46

Eotaxin

Nibbs et al., 1997

a

Values in parentheses indicate different results reported by different authors.

also revealed that the three charged amino acids at the C-terminus of human MIP-1 (amino acids 61, 65, 67) are not required for binding to CCR5 (Crisman et al., 1999). The downstream signaling pathways that mediate the effects of MIP-1 on cells remain largely uncharacterized. It has been reported that MIP-1 binding to CCR5 results in activation of the related adhesion focal tyrosine kinase (RAFTK), with subsequent activation of the cytoskeletal protein paxillin and the downstream transcriptional activators, JNK, SAPK, and p38 MAPK (Ganju et al., 1998). Maghazachi (1999) has demonstrated Pyk2 activation due to MIP-1 signalling through CCR5. A more thorough discussion of MIP-1 -mediated signaling can be found in the chapter reviewing CCR5 biology.

IN VITRO ACTIVITIES

In vitro findings MIP-1 CCR1 and CCR5, the primary receptors for MIP-1, are expressed on a broad range of cell types including

leukocytes, dendritic cells, endothelial cells, epithelial cells, and fibroblasts, hence the activities of MIP-1 are numerous and varied (Devalaraja and Richmond, 1999). MIP-1 was originally identified by its potent chemoattractant activity for monocytes in an in vitro Boyden chamber assay, and later was found to exert chemoattractant and/or adhesive effects on other cell types including CD8‡ lymphocytes, B cells, NK cells, dendritic cells, and eosinophils (Schall, 1994; Maghazachi and Al-Aoukaty, 1998; Dieu-Nosjean et al., 1999). The in vitro biological activities of MIP-1 extend far beyond that of chemotaxis, to regulating both hematopoietic and nonhematopoietic cell development, immune cell differentiation, and inflammatory cell activation. Table 7 lists some of the in vitro biological activities (organized by target cell) which are mediated by MIP-1. With respect to modulating the activation state of lymphocytes, MIP-1 has been reported to promote lymphocyte activation on the one hand (Taub et al., 1996), and to inhibit proliferation driven by anti-CD3 mAb and IL-2 production by splenic lymphocytes on the other hand (Zhou et al., 1993). The significance of these apparently opposing effects on lymphocytes is not clear, but recent studies using CCR5 knockout

MIP-1, MIP-1

1189

Table 7 In vitro biological activities of MIP-1 Target cell

MIP-1 action

References

Monocyte

Induces monocyte chemotaxis

Adams and Lloyd, 1997

Induces release of N-acetyl- -D-glucosamininidase from cytochalasin B-treated monocytes

Uguccioni et al., 1995

Upregulates CD11b/CD18 expression

Vaddi and Newton, 1994a

Induces monocyte transendothelial migration

Chuluyan et al., 1994

Upregulates tumoricidal activity, inflammatory cytokine release

Fahey et al., 1992

Induces trypanocidal activity

Villalta et al., 1998

Dendritic cell

Induces dendritic cell chemotaxis, stimulates Ca2‡ mobilization

Sozzani et al., 1997

T lymphocyte

Induces CD8‡ cell chemotaxis

Taub et al., 1993

Induces transendothelial migration

Furie and Randolf, 1995

Stimulates lymphocyte adhesion to ICAM, VCAM, ECM proteins

Lloyd et al., 1996

Induces TH1 chemotaxis/transmigration

Siveke and Hamann, 1998

Stimulates transmigration of / and / T cells

Roth et al., 1998

Drives TH0 to TH1 differentiation

Karpus and Kennedy, 1997

Induces TH0 cells to express TH1 cytokines

Karpus et al., 1997

Provides costimulation for T cell activation

Taub et al., 1996

Enhances T cell-mediated killing of listeria-infected target cells

Cook et al., 1999

Stimulates Ca2‡ mobilization

Loetscher et al., 1996

Stimulates release of granule-derived serine esterases

Loetscher et al., 1996

Induces generation of cytolytic cells (CHAK)

Maghazachi et al., 1996

Inhibits infection with M-tropic strains of HIV

Littman, 1998

Induces chemotaxis

Adams and Lloyd, 1997

Enhances IgE, IgG4 production

Kimata et al., 1996

Induces NK chemotaxis, adhesion

Maghazachi and Al-Aoukaty, 1998

Activates NK cells, enhances NK-mediated cytolysis, enzyme release

Taub et al., 1995

Neutrophil

Stimulates Ca2‡ mobilization

Zhang et al., 199

Eosinophil

Induces eosinophil chemotaxis, stimulates cationic protein release

Adams and Lloyd, 1997

Basophil

Induces basophil chemotaxis, stimulates histamine release

Adams and Lloyd, 1997

Mast cell

Induces mast cell chemotaxis

Adams and Lloyd, 1997

Stimulates mast cell degranulation

Alam et al., 1994

B lymphocyte NK cells

Osteoclast

Induces osteoclast chemotaxis

Kukita et al., 1992

Induces osteoclastogenesis on calcified matrices

Kukita et al., 1997

Keratinocyte

Inhibits proliferation

Parkinson et al., 1993

Schwann cells

Stimulates proliferation

Khan and Wigley, 1994

1190 Barbara Sherry and Giovanni Franchin

Table 7 (Continued ) Target cell

MIP-1 action

References

Astrocyte

Induces astrocyte chemotaxis

Hesselgesser and Horuk, 1999

Inhibits proliferation

Khan and Wigley, 1994

Induces microglia cell chemotaxis, induces actin cytoskeleton reorganization, alters distribution of F-actin

Cross and Woodroofe, 1999

Immature progenitor

Suppresses colony formation (CFU-A, CFU-S), induces cell cycle arrest

Owen-Lynch et al., 1998

(stem cell) Mature progenitor

Suppressing colony formation (CFU-GM, CFU-GEMM, BFU-E)

Rollins, 1997

Peripheral blood progenitor

Suppresses colony formation, increases adhesion to fibronectin

Durig et al., 1999

Enhances proliferation of cord blood CD34‡ progenitors

De Wynter et al., 1998

Cord blood progenitors

Induces long-term survival of peripheral blood progenitors in vitro

Egger et al., 1998

Spermatogenic cell

Inhibits DNA synthesis

Hakovirta et al., 1994

Tumor cell

Stimulates chemotaxis and cytoskeletal reorganization in breast cancer cell lines (MCF-7, ZR-751)

Youngs et al., 1997

Upregulates LFA-1 on adult T cell leukemia cells

Tanaka et al., 1998b

Stimulates TIL chemotaxis, stimulates TIL adhesion to stroma, stimulates TIL integrin expression (LFA-1, VLA-4)

Tanaka et al., 1998c

Microglia cell

Bone marrow progenitor

TIL (tumor infiltrating lymphocyte)

mice demonstrate enhanced production of both TH1and TH2-type cytokines, increased DTH responses, and increased humoral responses to T cell-dependent antigenic challenge, supporting a role for MIP-1, MIP-1 , and/or RANTES (via CCR5 activation) in downmodulating T cell-dependent immune responses (Ward and Westwick, 1998; Zhou et al., 1998). In addition to its other biological activities, MIP-1 has been show to play a role in activating MHCunrestricted killer cells (CHAK), an activity which could presumably be manipulated to therapeutic advantage for the treatment of cancer (Maghazachi et al., 1996). MIP-1 MIP-1 , like MIP-1, was originally identified by its potent chemoattractant activity for monocytes in an in vitro Boyden chamber assay, but was found later to attract a number of other cell types including CD4‡ lymphocytes, thymocytes, and dendritic cells (Schall, 1994; Sozzani et al., 1997). While MIP-1 was initially

characterized as a chemoattractant for activated CD4‡ cells, it has recently been shown to selectively attract TH1 type, versus TH2 type, effector cells (Siveke and Hamann, 1998). This observed selectivity for TH1-type cells most likely results from the preferential expression of CCR5 (MIP-1 receptor) on TH1-type cells (Ward and Westwick, 1998), and suggests a potential role for MIP-1 in directing host responses along a proinflammatory path. Its range of biological activities is now known to extend far beyond the realm of chemotaxis (Rollins, 1997; Ward and Westwick, 1998). MIP-1 attracts CD4‡, CD8‡, and double positive thymocyte subsets, and induces mobilization of intracellular calcium, phosphorylation of protein tyrosine, and activation of the mitogen-activated protein kinase (MAPK) pathway in these cells. These activities suggest that MIP-1 may play a role in trafficking and/or development of lymphoid progenitors in primary lymphoid tissues (Dairaghi et al., 1998; Kim and Broxmeyer et al., 1999b). MIP-1 can also mediate lymphocyte adhesion to the endothelium and subsequent

MIP-1, MIP-1 dose-dependent transmigration into tissues (Taub et al., 1993; Tanaka et al., 1998a). In addition to its other biological activities, MIP-1 (like MIP-1) has been shown to induce the proliferation and activation of CD56‡ (NK) cells which, upon activation, have the ability to kill fresh and explanted tumors in a MHC-unrestricted and antigen nonspecific fashion (Maghazachi et al., 1996). This suggests a potential role for MIP-1 in host antitumor responses.

Regulatory molecules: Inhibitors and enhancers Incubation of monocytes with opiates (e.g. metenkephalin, morphine) blocks their ability to respond to MIP-1. Opiate-mediated inhibition of MIP-1 responses was found to be mediated through  and  receptors, and not to involve inhibition of binding (Grimm et al., 1998). Chemotaxis in response to MIP1 was not effected by opiate pretreatment, suggesting that opiate pretreatment cross-desensitized CCR1, but not CCR5.

Bioassays used MIP-1 There are two bioassays commonly used to assess the activity of native and recombinant MIP-1. The first measures the activity of MIP-1 to attract cultured monocytes in a Beydon chamber assay (Falk et al., 1980; Wang et al., 1993). When assaying purified natural or recombinant MIP-1, the ED50 for monocyte chemotactic activity is typically 2±10 ng/mL. The second commonly used bioassay measures the activity of MIP-1 to inhibit hematopoietic stem cell proliferation in an in vitro colony-forming assay (CFU-A) that detects primitive stem cells (Graham et al., 1990). When assaying purified natural or recombinant MIP-1 the ED50 for the CFU-A effect is typically 2±5 ng/mL when murine bone marrow cells are used as targets. MIP-1 The most commonly used bioassay for MIP-1 activity is the monocyte chemotaxis assay. In this assay the activity of MIP-1 to attract cultured monocytes is measured in a modified Boyden chamber (Falk et al., 1980; Wang et al., 1993). Typically 2±10 ng/mL is the ED50 for monocyte chemotactic activity for purified natural or recombinant MIP-1 .

1191

IN VIVO BIOLOGICAL ACTIVITIES OF LIGANDS IN ANIMAL MODELS

Normal physiological roles Exogenous administration of MIP-1 and MIP-1 , passive neutralization of endogenous MIP-1 and/or MIP-1 responses, and gene knockout studies in animal models of inflammation all support the hypothesis that MIP-1 and MIP-1 perform specific, although sometimes overlapping, functions in normal homeostasis and in host-protective and pathologic inflammatory responses. Animal models in which the expression and/or involvement of either MIP-1 or MIP-1 have been demonstrated are listed in Table 8 and Table 9, respectively, and the role of these chemokines in representative models is discussed below. Role of MIP-1 and MIP-1 in Homeostatic Functions While the primary function of MIP-1 and MIP-1 appears to be as regulators of the host response to invading pathogens, several discoveries have suggested that one or both of these molecules may play a role in normal homeostatic functions as well. Areas in which a role for MIP-1 and/or MIP-1 has been suggested are hematopoietic cell development (Kukita et al., 1997), keratinocyte development (Parkinson et al., 1993), bone remodeling (Kukita et al., 1997; Scheven et al., 1999), germ cell development (Hakovirta et al., 1994), and regulation of cellular trafficking to lymphoid tissues (Kelner and Zlotnik, 1995; Dairaghi et al., 1998). A role for MIP-1 in normal hematopoietic cell development has been hypothesized based upon the observation that MIP1, which has been shown to regulate hematopoietic cell development in vitro and in vivo, was found to be constitutively expressed at high levels in eosinophilic myelocytes within the bone marrow compartment (Kukita et al., 1997). A potential role for MIP-1 in bone remodeling is suggested by the observation that MIP-1, which has been shown to enhance osteoclast differentiation (Scheven et al., 1999) and induce osteoclastogenesis on calcified matrices in the absence of any other osteotropic hormones (Kukita et al., 1997), is constitutively expressed by osteoblasts (in particular by those in the vicinity of osteoclasts) at sites of bone remodeling (Kukita et al., 1997). In rats, MIP-1 expression has been detected in tissues from every spermatogenic stage of rat seminiferous epithelium (Hakovirta et al., 1994). This observation, combined with in vitro studies by these same

1192 Barbara Sherry and Giovanni Franchin

Table 8 Animal disease models in which MIP-1 expression (mRNA or protein) has been detected Animal disease model

Cell/tissue localization

MIP-1 expression correlates with:

References

Endotoxemia (mu, rat)

Lung, liver, serum

inflammatory cell infiltration/ decreased survival

Standiford et al., 1995

Cecal ligation and puncture (mu)

Liver, lung

PMN/macrophage infiltration

Salkowski et al., 1998

Bacterial meningitis (mu)

Meninges (PMN, macrophages)

PMN influx, disease severity

Diab et al., 1999

Turpentine-induced tissue damage (mu)

Peritoneum

magnitude of cellular infiltrate

Fantuzzi and Dinarello, 1998

Zymosan-induced peritonitis (mu)

Peritoneum

magnitude of cellular infiltrate

Fantuzzi and Dinarello, 1998

Spinal cord injury (mu)

CNS (microglia)

Inflammatory diseases

Xia and Hyman, 1999

Focal ischemia (rat)

CNS (microglia/astrocytes)

Excisional wounding (mu)

Wound macrophages

intensity of macrophage infiltrate, collagen synthesis

Xia and Hyman, 1999 Di Pietro et al., 1998

Irritant peritonitis (mu)

Peritoneal macrophages

PMN influx

Wu et al., 1999

Infectious diseases L. donovani infection (mu)

Liver (Kupffer cells)

Cotterell et al., 1999

S. mansoni infection (mu)

Granuloma

granuloma formation

Hesselgesser and Horuk, 1999

L. monocytogenes infection (mu)

Spleen (CD 8 T cells)

clearance of bacteria

Cook et al., 1999

P. carinii infection (mu)

Lung

acute stage infection

Wright et al., 1999

PMN infiltration

P. aeruginosa infection (mu)

Resident corneal cells

SIV infection (pri)

Brain endothelium, microglia

Wright et al., 1999

Influenza virus infection (mu)

Lung (MNC)

degree of pulmonary edema

Cook, 1996

Coxsackie virus infection (mu)

Heart, infiltrating MNCs

severity myocarditis

Cook et al., 1995

Wright et al., 1999

Granulomatous lung disease Bleomycin-induced lung injury (rat)

Alveolar/interstitial macrophages, fibroblasts

Smith et al., 1994

Autoimmune disease Experimental allergic encephalitis (mu)

Spinal cord (infiltrating PBL), brain

acute onset/disease severity

Glabinski et al., 1998; Hesselgesser and Horuk, 1999

Type II collagen-induced arthritis (mu)

Inflamed joint (M, Ch, F)

incidence/magnitude arthritis

Strieter et al., 1996; Campbell et al., 1998

GVHD-associated liver injury (mu)

Infiltrating MNCs, endothelial, epithelial

disease course

Murai et al., 1999

Crescentic glomerulonephritis (rat)

Glomeruli

onset inflammatory cell infiltration

Natori et al., 1997

Autoimmune sialoadenitis (mu)

Submandibular gland (infiltrating MNCs)

disease progression

Mustafa et al., 1998

Immune complex-mediated lung injury (rat)

BAL fluid

PMN influx/increased vascular permeability

Ward, 1996

MIP-1, MIP-1

1193

Table 8 (Continued ) Animal disease model

Cell/tissue localization

MIP-1 expression correlates with:

References

Experimental allergic neuritis (rat)

Infiltrating T cells

acute infection

Fujioka et al., 1999

Allergen-induced airway disease (mu)

Lung, mucosal MNCs, airway epithelium

eosinophil infiltrate

Strieter et al., 1996

Allergic disease

BAL, bronchoalveolar lavage; CSF, cerebrospinal fluid; F, fibroblasts; MNC, mononuclear cells; Ch, chondrocytes; PBMC, periperal blood mononuclear cells; RSV, respiratory syncytial virus; M, macrophage; F, fibroblast; mu, murine; pri, primate.

Table 9 Animal disease models in which MIP-1 expression (mRNA and/or protein) has been detected Animal disease model

Cell/tissue localization

MIP-1 expression correlates with:

References

Endotoxemia (mu, rat)

Lung, liver, serum, AH/POA

acute infection/ fever

Minano et al., 1996a, 1996b

Bacterial meningitis (mu)

Meninges (infiltrating PMN, MNC)/CSF

Seebach et al., 1995

Cecal ligation and puncture (mu)

Lung/liver

PMN/macrophage infiltratron

Salkowski et al., 1998

Spinal cord injury (mu)

CNS (microglia)

inflammatory cell infiltration

Xia and Hyman, 1999

Cerebral stab injury (mu)

Brain (microglia)

degree leukocyte infiltration

Mennicken et al., 1999

SIV (pri)

BAL fluid, brain (endothelium,microglia)

peak viremia

Caufour et al., 1999; Hesselgesser and Horuk, 1999

Pseudomonas aeruginosa infection (cornea) (mu)

Resident corneal cells

PMN infiltration

Kernacki et al., 1998

Pneumocystis carinii infection (mu)

Lung

acute stage infection

Wright et al., 1999

E. coli pyelonephritis (mu)

Kidney, draining LN, spleen

inflammatory cell infiltration

Rugo et al., 1992

Experimental allergic encephalitis (mu)

Brain (infiltrating MNC, microglia), spinal cord

inflammatory cell infiltration

Hesselgesser and Horuk, 1999, Calabresi, 1999

Crescentic glomerulonephritis (rat)

Glomeruli

onset inflammatory cell infiltration

Natori et al., 1997

Liver allograft (mu)

Biliary epithelium, graft endothelium, graft infiltrating leukocytes

graft rejection

Adams et al., 1996

Autoimmune sialoadenitis (mu)

Submandibular glands

MNC infiltration

Mustafa et al., 1998

Experimental allergic neuritis (rat)

Infiltrating T cells

acute infection, clinical severity

Fujioka et al., 1999

Hapten (DNFB)-induced contact hypersensitivity (mu)

Lymph node (mast cells)

CD8, CD4 accumulation in LN

Tedla et al., 1998

Inflammatory diseases

Infectious diseases

Autoimmune diseases

Allergic diseases

BAL, bronchoalveolar lavage; CSF, cerebrospinal fluid; PBMC, periperal blood mononuclear cells; RSV, respiratory syncytial virus; PMN, polymorphonuclear cells; MNC, mononuclear cell; LN, lymph node; mu, murine; pri, primate.

1194 Barbara Sherry and Giovanni Franchin investigators which demonstrated that MIP-1 stimulates DNA synthesis in primitive (type A) spermatogonia and inhibits DNA synthesis in more differentiated (type B) spermatogonia, suggests that this chemokine may be a local regulator of mitotic and meiotic DNA synthesis in developing germ cells. Lastly, recent studies have suggested a role for both MIP-1 and/or MIP-1 in thymic development and the normal regulation of cellular trafficking to lymphoid tissues (Kelner and Zlotnik, 1995; Dairaghi et al., 1998). Even though MIP-1 and MIP-1 may indeed participate in the normal homeostatic processes discussed above, there must be considerable redundancy in these areas, as evidenced by the fact that no overt abnormalities in hematopoiesis, bone growth or development, or lymphocyte homing to lymphoid tissues are observed in mice in which the genes encoding either MIP-1 or CCR5 (MIP-1/MIP-1 receptor) have been removed by targeted gene deletion (Locati and Murphy, 1999). Mice in which the CCR1 (MIP-1 receptor) gene has been removed by targeted deletion, although viable, exhibit abnormalities in the induced trafficking and proliferation of hematopoietic progenitor cells (Locati and Murphy, 1999), suggesting a less redundant role for MIP-1, RANTES, and/or MCP-2 (CCR1 ligands) in normal hematopoietic development. Role of MIP-1 and MIP-1 in Modulating Host-protective Inflammatory Responses The leukocyte attractant and activating properties of MIP-1 and MIP-1 make them logical candidates for involvement in modulating host-protective inflammatory responses against bacterial, viral, and fungal pathogens. Targeted gene deletion and antibody neutralization studies have now confirmed a role for MIP1 in these processes. Studies in MIP-1 knockout mice demonstrated that host MIP-1 responses are critical in mounting a successful antiviral response against both influenza virus and Coxsackie virus (Cook, 1996). By comparing the course of murine cytomegalovirus (MCMV) infection in wild-type and MIP-1 knockout mice, Salazar-Mather et al. demonstrated that endogenously produced MIP-1 is required for the recruitment and activation of NK cells in this disease model, and for the establishment of a successful host protective antiviral response (SalazarMather et al., 1998). In active cryptococcal infection in mice (initiated by intratracheal inoculation of C. neoformans), MIP-1 was shown by antibody neutralization studies to be required for maximal leukocyte recruitment into the lungs, and for the establishment of cell-mediated immunity (Huffnagle et al., 1997).

MIP-1 has also been shown to participate in host antiviral responses in the CNS. For example, a recent study demonstrated that MIP-1 is a major mediator of leukocyte recruitment into the CNS compartment during C. neoformans infection and functions to clear disseminated infection (Huffnagle and McNeil, 1999). The leukocyte attractant and activating properties of MIP-1 and MIP-1 make them logical candidates for involvement in host antitumor responses that have an inflammatory component as well. Pathophysiological Roles As discussed above, MIP-1 and MIP-1 clearly play an important role in regulating the host response to invasion. But a growing body of correlative evidence supports the hypothesis that their overproduction in certain instances may underlie disease-related pathology (see Table 8 and Table 9). While correlative evidence is suggestive, it does not prove causality. Evidence for a causal role must come from studies in which the production or action of MIP-1 and/or MIP-1 is blocked in a particular disease state, with the observation of decreased pathology. Blocking of MIP-1 and/or MIP-1 responses can be achieved either passively, by neutralization of endogenously secreted peptides with specific antibodies, or directly, by knocking out the gene encoding the peptide itself (for results of such studies see Table 10). As can be seen from Table 10, such a causal connection between MIP-1 and MIP-1 release and disease-related pathology has been made in a number of animal disease models in which there is a destructive inflammatory component (e.g. arthritis, autoimmune encephalitis, schistosomiasis). This may be best illustrated by the observation that MIP-1 knockout mice are completely resistant to Coxsackie virusinduced myocarditis (Cook, 1996). Taken together, these results suggest that interfering with MIP-1 and/or MIP-1 responses might prove beneficial in human diseases that have an injurious inflammatory component. An alternative approach to assessing the contribution of endogenously produced MIP-1 and/or MIP1 to disease-related pathology entails interfering with the ability of these molecules to interact with their receptors (by targeted gene deletion or the use of receptor antagonists). While this approach can reveal previously unrecognized roles for these molecules, the fact that MIP-1 and MIP-1 share receptors with one another, as well as with other CC chemokines, makes the results somewhat difficult to interpret. Results of studies with CCR1 knockout mice suggest a potential role for MIP-1 in pancreatitis-induced pulmonary infection and schistosome egg-induced

Table 10

Results of interfering with MIP-1 or MIP-1 actions in vivo

Blocking strategy

Target disease

Result of blocking endogenous MIP-1 or MIP-1 response

References

Coxsackie virus infection

Impaired inflammatory response, decreased pathology

Cook et al., 1995

Targeted gene disruption MIP-1ÿ/ÿ mouse

Influenza virus infection

Impaired inflammatory response, decreased pathology

Cook et al., 1995

MCMV infection

Reduced NK cell migration to liver, decreased resistance to viral infection

Salazar-Mather et al., 1998

HSV-1 infection (cornea)

Reduced ocular inflammation (no effect viral clearance)

Tumpey et al., 1998

Cryptococcal infection

Decreased survival/TH1 response/clearance from brain

Huffnagle and McNeil, 1999

Allograft rejection

Delayed graft rejection

Bacon and Oppenheim, 1998

Endotoxemia

Reduced neutrophil/macrophage inlfiltrate into lung, decreased lung permeability/decreased mortality

Standiford et al., 1995

Bleomycin-induced lung fibrosis

Reduced inflammatory cell accumulation, reduced pulmonary fibrosis

Smith, 1996

Pneumococcal meningitis

Delayed onset CSF leukocytosis

Saukkonen et al., 1990

Cryptococcal infection

Reduced monocyte/neutrophil influx into lung, decreased clearance of pathogen

Huffnagle et al., 1997

Schistosomiasis

Decreased pulmonary granulomas

Lukacs et al., 1993b

Antibody neutralization Anti-MIP-1

Strieter et al., 1996 Karpus and Kennedy, 1997

Experimental autoimmune neuritis (EAN)

Reduced macrophages in sciatic nerves, decreased inflammation and demyelination

Zou et al., 1999

Allergic airway inflammation

Decreased eosinophil infiltration into lung

Strieter et al., 1996

Allergic peritonitis

Reduced PMN infiltration

Das et al., 1999

Immune complex-mediated lung injury

Decreased BAL fluid PMN, decreased vascular permeability, decreased BAL fluid TNF

Ward, 1996

Hapten (DNFB)-induced contact sensitivity

Reduced T lymphocyte trafficking to lymph node

Tedla et al., 1998

Dermal wound healing

Impaired macrophage recruitment, decreased wound angiogenic activity, decreased collagen synthesis

Di Pietro et al., 1998

Graft-versus-host-disease (GVHD)

Reduced liver injury

Murai et al., 1999

Endotoxemia

Blunted fever response

Minano et al., 1996a, 1996b

Hapten (DNFB)-induced contact sensitivity

Reduced T lymphocyte trafficking to lymph node

Tedla et al., 1998

CNS, central nervous system; CSF, cerebrospinal fluid.

1195

Decreased incidence, decreased joint inflammation Inhibition acute disease development, decreased mononuclear cell infiltration in CNS

MIP-1, MIP-1

Anti-MIP-1

Collagen-induced arthritis Experimental autoimmune encephalitis (EAE)

1196 Barbara Sherry and Giovanni Franchin granuloma formation (Locati and Murphy, 1999). Results of studies with CCR5 knockout mice suggest a potential role for MIP-1 and/or MIP-1 in GVHD-associated liver injury and LPS-induced mortality (Locati and Murphy, 1999; Zhou et al., 1998). A more detailed discussion of these approaches can be found in individual chapters reviewing CCR1 and CCR5 biology.

Species differences With respect to the biological activities mediated by MIP-1, the only major species difference that has been reported is that murine MIP-1 is a potent eosinophil chemoattractant, while human MIP-1 is only weakly chemotactic for that cell type (Rot et al., 1992). This discrepancy may result from the fact that murine MIP-1 has been reported to bind murine CCR3 with high affinity (Post et al., 1995), while human MIP-1 is not a ligand for human CCR3 and therefore must mediate its eosinophil chemoattractant effects via binding to another receptor, possibly CCR1 (Pease et al., 1998; Devalaraja and Richmond, 1999). With respect to its cellular recruitment and activation properties, MIP-1 has been shown to elicit similar responses in mice, rats, dogs, monkeys, and man (Baggiolini et al., 1994). In both mouse and man MIP-1 enhances the proliferation of mature progenitor cells (Broxmeyer et al., 1990), and suppresses the proliferation of immature progenitors (Broxmeyer et al., 1999b). To date, there have been no reports detailing major functional differences between species for MIP-1 .

Knockout mouse phenotypes MIP-1 knockout mice (Cook et al., 1995), had no gross abnormalities in development or in the histology of any major organ. No significant differences between wild-type and MIP-1 knockout mice were observed by these investigators in peripheral blood (hematocrits, total white blood cell counts, and differential counts), bone marrow (progenitor number), spleen or lymph nodes (T and B cell numbers). These results indicate that MIP-1 is not essential for normal hematopoietic cell development. Differences were observed, however, in the responses of wild-type and MIP-1 knockout mice to viral infection. When knockout mice were infected with influenza virus, recruitment of CD8‡ T cells into the infected lung was significantly reduced as compared with that seen in wild-type mice (Cook et al., 1995). This failure to recruit CD8‡ T cells to the lung resulted in a less severe infection-associated

pneumonitis, and a pronounced delay in resolution of the viral infection. When MIP-1 knockout mice were infected with Coxsackie virus they failed to develop the profound myocarditis normally associated with that disease (Cook et al., 1995). These data demonstrated that MIP-1 is required for a normal inflammatory response to these, and possibly other, viruses, and suggested that agents that inhibited the actions of MIP-1 might prove useful for controlling inflammation in certain settings. More recently, MIP1 knockout mice have been shown to have altered responses to several other viruses including MCMV and HSV, and to fungi (Salazar-Mather et al., 1998; Tumpey et al., 1998; Huffnagle and McNeil, 1999).

Transgenic overexpression No transgenic overexpression models have been reported for either MIP-1 or MIP-1 .

Interactions with cytokine network MIP-1 and MIP-1 are pleiotropic molecules and their biological effects in vivo are determined not only by the timing and location of their expression, but also by the milieu into which they are released. Both peptides are up upregulated in a number of animal disease models (see Table 8 and Table 9), but the magnitude and temporal duration of their responses are often controlled by the actions of other endogenously produced cytokines, which together comprise the cytokine network. TNF and MCP-1 have been shown to enhance MIP-1 antifungal responses to cryptococcal infection in mice (Huffnagle et al., 1997). These two cytokines exert their enhancing activity by upregulating the expression of MIP-1 in response to cryptococcal challenge. In two models of local inflammation, turpentine-induced tissue damage and zymosaninduced peritonitis, MIP-1 responses are suppressed in stem cell factor (SCF)-deficient mice, suggesting that this cytokine may be an endogenous cytokine enhancer of MIP-1 action (Fantuzzi and Dinarello, 1998). Whether SCF enhances MIP-1 responses directly, or whether MIP-1 responses are enhanced by cytokines released by mast cells which are known to be depleted in SCF-deficient mice, is not clear. Another endogenous cytokine enhancer is IFN which has been shown to potentiate MIP-1 release by alveolar macrophages during allergic reactions (Dery and Bissonnette, 1999). A subset of cytokines has been shown to suppress MIP-1 responses in several animal models. Ajuebor et al. have

MIP-1, MIP-1 demonstrated the existence of a negative feedback loop between MIP-1 expression and function and endogenously produced IL-10 in an acute inflammatory response induced by intraperitoneal injection of zymosan (Ajuebor et al., 1999). Similarly, IL-10 and IL-4 have been identified as endogenous cytokine inhibitors of MIP-1 responses in an IgG immune complex model of lung injury (Ward, 1996). MIP-1 has been shown to regulate the expression of other inflammatory cytokines as well. For example, TNF and IL-6 production in response to C. neoformans infection in mice is stimulated by endogenously produced MIP-1 (Huffnagle et al., 1997).

Endogenous inhibitors and enhancers MIP-1 The enhancing effects of endogenously produced cytokines on MIP-1 production and action have been described above. Studies by Kim et al. suggest that ICAM-1 and LFA-3 are endogenous enhancers of MIP-1 responses, most probably by providing T cell costimulation in vivo (Kim et al., 1999). In collagen-induced arthritis in mice, the observation that adenosine receptor agonists block the release of MIP-1 in the paw thereby suppressing MIP-1mediated neutrophil infiltration (Szabo et al., 1998), suggests that adenosine, a purine nucleoside which is released in response to metabolic stress and shown to exert anti-inflammatory actions, may be an endogenous inhibitor of MIP-1 responses in this model. MIP-1 Studies by Kim et al. (1999) suggest that ICAM-1 and LFA-3 are endogenous enhancers of MIP-1 responses, most probably by providing T cell costimulation in vivo.

PATHOPHYSIOLOGICAL ROLES IN NORMAL HUMANS AND DISEASE STATES AND DIAGNOSTIC UTILITY

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several exceptions to this generalization. In humans, constitutive expression of MIP-1 has been detected in eosinophilic granules within the bone marrow compartment (Kukita et al., 1997). The significance of this constitutive production is not presently known, although the activity of these two mediators to modulate the development of hematopoietic progenitor cells suggests that they may play a role in the normal regulation of hematopoietic cell development. MIP-1 has also been shown to be constitutively expressed in osteoclasts in the bone (Kukita et al., 1997), where basal levels in osteoclasts and osteoblasts may play an important role in bone remodeling and wound healing processes.

Role in experiments of nature and disease states Levels of both MIP-1 and MIP-1 are markedly upregulated when human subjects are exposed to certain pathogens, and the expression profiles and clinical correlation of MIP-1 and MIP-1 expression in specific disease states are summarized in Table 11 and Table 12. Although the contribution of endogenously produced MIP-1 and MIP-1 to host inflammatory responses is not completely understood, its activity to selectively attract specific subpopulations of lymphocytes has been shown to have a major impact on outcome in a range of disease states. One of the best examples of this activity of MIP-1 and MIP-1 to selectively mold inflammatory responses can be seen in patients with rheumatoid arthritis, where the production of these two peptides in the synovium leads to an abnormally high representation of CCR5‡ T cells in synovial fluids (> 85%) as compared with blood or lymphoid tissues (5±10%) (Ward and Westwick, 1998). Since TH1 cells have been shown to preferentially express CCR5, this is one mechanism by which MIP-1 and MIP-1 can, through the selective recruitment of CCR5-expressing cells, favor the development of TH1 responses.

IN THERAPY

Normal levels and effects

Preclinical ± How does it affect disease models in animals?

In humans, the levels of MIP-1 and MIP-1 normally present in the tissues are low, or undetectable in the absence of an activating stimulus. There are

The ability of MIP-1 to inhibit hematopoietic stem cell proliferation both in vitro and in vivo raised the hope that it might be used therapeutically to protect

Human diseases in which MIP-1 expression (mRNA and/or protein) has been demonstrated

Disease

Site of detection

Method

Clinical correlations

References

Gram-negative bacterial sepsis

Serum

EIA

Acute infection (not prognostic)

O'Grady et al., 1999

Bacterial meningitis

CSF

EIA

Chemotactic activity in CSF

Spanaus et al., 1997

PBMC pro-virus load

Iverson et al., 1998

Infectious diseases

Blood

EIA

Cervix

EIA

Alveolar macrophages

PCR

CD8 alveolitis

Denis and Ghadirian, 1994

Brain (microglia)/CSF

PCR

HIV encephalitis/dementia

Schmidtmayerova et al., 1996; Letendre et al., 1999

Lymph node (resident macrophages)

IH

Increased lymph node CD8 counts

Lower airway epithelium

IH

Eosinophil cationic protein levels

Nasal secretions

EIA

Adenovirus infection

Nasal secretions

EIA

Bonville et al., 1999

Influenza infection

Nasal secretions

EIA

Bonville et al., 1999

Parainfluenza infection

Nasal secretions

EIA

Bonville et al., 1999

Herpes simplex virus infection

Lesion site/ vesicle fluid

EIA

Late CD8 infiltrate

Mikloska et al., 1998

Cutaneous leishmaniasis

Lesion site

PCR

Nonhealing, diffuse lesions

Ritter et al., 1996

Helicobacter pylori infection

Antral mucosa (macrophages)

PCR/IF

Kusugami et al., 1999

Plasmodium falciparum infection

Serum

EIA

Burgmann et al., 1995

Sarcoidosis

BAL cells/plasma

EIA

Lymphocytic infiltrate/disease progression/eosinophil counts

Oshima et al., 1999; Ziegenhagen et al., 1998

Hypersensitivity pneumonitis

BAL cells

PCR

Inflammatory cell infiltration

Oshima et al., 1999

Cryptogenic fibrosing alveolitis

BAL cells

PCR

Inflammatory cell infiltration

Oshima et al., 1999

Idiopathic pulmonary fibrosis

BAL/lung

PCR

Disease progression/eosinophil counts

Ziegenhagen et al., 1998

SF PMNs/macrophages

PCR/IH/ EIA/PCR

Disease severity/ MNC counts

Hatano et al., 1999

ST MNC/fibroblast

PCR

HIV/AIDS

RSV bronchiolitis

Domachowske and Rosenberg, 1999; Harrison et al., 1999

Granulomatous lung diseases

Autoimmune diseases Rheumatoid arthritis

Lisignoli et al., 1999

1198 Barbara Sherry and Giovanni Franchin

Table 11

Bone marrow stroma

PCR

Multiple sclerosis

Brain (microglia)/CSF

IH/EIA

Active/progressing disease

Balashov et al., 1999; Karpus and Ransohoff, 1998

Dermatomyositis

Muscle

PCR

Disease activity

Mikloska et al., 1998

Polymyositis

Muscle

PCR

Disease activity

Mikloska et al., 1998

Ulcerative colitis

Colonic epithelial cells

IH

Diagnosis

Vainier et al., 1998

Leukocytes

IH

Colonoscopy, sLe(x) Allergic diseases

Asthma (antigen-challenged)

Sputum

EIA

Late phase exacerbation

Kurashima et al., 1996

PBMCs/BAL fluid

EIA

Poor responders/CD4 accumulation

Hsieh et al., 1996

Metastatic breast cancer

Lymph node

IH/ISH

Presence M,L

Tedla et al., 1999

Hodgkin's lymphoma

Tumor/inflammatory cells

IH

EBV infection in neoplastic cells

Hepatocellular carcinoma

Tumor endothelium/tumor

IH

Yoong et al., 1999

Colorectal hepatic metastasis

Tumor endothelium/tumor

IH/EIA

Yoong et al., 1999

Stromal tissue

IH

Yoong et al., 1999

Tumor

PCR

Ishii et al., 1998

Respiratory distress syndrome

BAL

IH

Poor outcome/degree fibrosis

Murch et al., 1996

Congestive heart failure

Serum monocyte fraction

EIA

Class IV disease inversely correlated with left ventricular ejection fraction

Aukrust et al., 1998

Neoplastic diseases

Astrocytoma

Teruya-Feldstein et al., 1999

Other

BAL, bronchoalveolar lavage; CSF, cerebrospinal fluid; MNC, mononuclear cell; PBMC, periperal blood mononuclear cells; RSV, respiratory syncytial virus; SF, synovial fluid; ST, synovial tissue; IH, immunohistochemistry; ISH, in situ hybridization; EIA, Enzyme-linked immunoassay.

MIP-1, MIP-1 1199

1200 Barbara Sherry and Giovanni Franchin

Table 12

Human diseases in which MIP-1 expression (mRNA and/or protein) has been detected

Disease

Site of detection

Method

Clinical correlations

References

Gram-negative bacterial sepsis

Serum

EIA

Acute infection (not prognostic)

O'Grady et al., 1999

Bacterial meningitis

CSF

EIA

MNC chemotactic activity

Spanaus et al., 1997

Tuberculosis

Serum

EIA

Active infection

Juffermans et al., 1999

Recurrent herpes simplex infection

Vesicle fluid

EIA

Early CD4 predominance

Mikloska et al., 1998

HIV/AIDS

Serum Cervix

EIA

Cervical viral DNA load

Iversen et al., 1998

Brain (microglia, astrocytes)

PCR

HIV encephalitis

Schmidtmayerova et al., 1996; Letendre et al., 1999

CSF

PCR

Dementia

Lower airway epithelium

IH

Eosinophil cationic protein

Nasal secretions

EIA

Adenovirus infection

Nasal secretions

EIA

Bonville et al., 1999

Influenza infection

Nasal secretions

EIA

Bonville et al., 1999

Parainfluenza infection

Nasal secretions

EIA

Bonville et al., 1999

Toxoplasmosis

Lymph node

IH/ISH

Tedla et al., 1999

Sinus histiocytosis

Lymph node

IH/ISH

Severe follicular hyperplasia

Tedla et al., 1999; Tanaka et al., 1993

Sarcoidosis

BAL cells

PCR

Inverse correlation CD4/CD8 ratio

Oshima et al., 1999

Hypersensitivity pneumonitis

BAL cells

PCR

Inverse correlation CD4/CD8 ratio

Oshima et al., 1999

Cryptogenic fibrosing alveolitis

BAL cells

PCR

Inverse correlation CD4/CD8 ratio

Oshima et al., 1999

Alzheimer's disease

Reactive astrocytes

IH

Associated with amyloid deposits

Xia and Hyman, 1999

Multiple sclerosis

Brain (microglia)

IH

Increased migratory capacity of MS-derived PBLs (active disease)

Calabresi et al., 1999

Dermatomyositis

Muscle

PCR

Disease activity

Adams et al., 1997

Infectious disease

RSV bronchiolitis

Harrison et al., 1999

Granulomatous lung disease

Autoimmune disease

Polymyositis

Muscle

PCR

Disease activity

Adams et al., 1997

Rheumatoid arthritis

ST joint (lining cells)

IH

Lymphocyte infiltration, cell proliferation

Robinson et al., 1995

T cells (SF, blood)

PCR

Diagnosis

SF

EIA

SF chemoattractivity

ST, lining cells, M, SMC, endo

IH

Diagnosis

Osteoarthritis

Inflammatory bowel disease

Mucosa (M,L,endo)

Koch et al., 1995

Luster, 1998

MIP-1, MIP-1

Table 12

1201

(Continued )

Disease

Site of detection

Method

Tumor endothelium

IH

Tumor

IH

Tumor endothelium/tumor

IH/EIA

Stromal tissue

IH

Tumor/cyst fluid

PCR/EIA

Clinical correlations

References

Neoplastic disease Hepatocellular carcinoma Colorectal hepatic metastasis Astrocytoma

Yoong et al., 1999 Yoong et al., 1999

Ishii et al., 1998

BAL, bronchoalveolar lavage; CSF, cerebrospinal fluid; PBMC, peripheral blood mononuclear cells; RSV, respiratory syncytial virus; IH, immunohistochemistry; EIA, enzyme-linked immunoassay; SF, synovial fluid; ST, synovial tissue; MNC, mononuclear cells; M, macrophage; L, lymphocyte; endo, endothelial cells; SMC, smooth muscle cell.

both the quality of the stem cell population and its capacity to reconstitute itself after treatment with cytotoxic drugs. A significant amount of progress has now been made in assessing whether this type of approach will achieve clinical benefit. The effects of exogenous administration of MIP-1 and BB-10010, a nonaggregating MIP-1 analog, on chemotherapyinduced myelotoxity in animals are discussed in the next subsection. Exogenous administration of MIP-1 or BB-10010 has yet to be tested for clinical benefit in any other animal disease models. Results obtained from studies using mice in which the MIP-1 gene has been removed by targeted gene deletion suggest the potential clinical utility of MIP-1 (or BB-10010) administration in select animal models of viral infection in which MIP-1 has been shown to stimulate host antiviral responses (Locati and Murphy, 1999). On the other hand, the potent inflammatory properties of MIP-1 argue that its administration in animal disease models with a negative inflammatory component (e.g. arthritis, autoimmune encephalitis) might exacerbate, rather than lessen, disease-associated injury. The clinical utility of exogenous MIP-1 administration has not yet been tested. Another potential use of MIP-1 (and its analogs) and/or MIP-1 is in HIV disease, where CCR5 is a critical coreceptor for viral entry into susceptible target cells. Although the utility of this approach has been demonstrated in vitro, it has not yet been tested in vivo (Proudfoot et al., 1999). An alternative, MIP1-based, anti-HIV approach has been identified (Yang et al., 1997). In this approach the MIP-1 gene is modified in such a way that newly synthesized protein contains an added KDEL sequence at its Cterminus trapping it in the endoplasmic reticulum where it can bind to and prevent newly synthesized

CCR5 from exiting the endoplasmic reticulum and trafficking to the cell surface. This approach has been tested in cultured cells and found to render them resistant to HIV infection (Yang et al., 1997). This type of `intracrine' approach is now being developed for potential clinical use (Bai et al., 1998). To date, most of the preclinical studies undertaken in experimental animals have been designed to block the harmful actions of endogenously produced MIP-1 or MIP-1 . For simplicity, these alternative therapeutic strategies targeting pathological consequences of MIP-1 and/or MIP-1 are discussed separately at the end of this section. None of these strategies has yet progressed to the stage of clinical testing.

Effects of therapy: Cytokine, antibody to cytokine inhibitors, etc. In an effort to avoid complications related to the tendency of MIP-1 to form large molecular weight aggregates, many of the preclinical studies ± and all of the clinical studies performed to date ± have used the MIP-1 analog, BB-10010, in lieu of MIP-1. BB10010 is a genetically modified form of human MIP1 in which a single amino acid substitution has been made (aspartate to alanine at position 26). This change results in a molecule which, unlike native MIP-1, does not readily aggregate (Williams et al., 1997). BB-10010 and MIP-1 are equipotent when assayed in vitro for stem cell-suppressing activity. Before its use in animal models or in humans, BB10010 was assessed against wild-type MIP-1 for effects on phagocyte function in macrophages and neutrophils in vitro (Williams et al., 1997). In both cell

1202 Barbara Sherry and Giovanni Franchin types, BB-10010 and MIP-1 mobilized calcium with identical dose±response curves. Neither directly stimulated phagocyte superoxide production, nor did they have any priming effect on agonist-induced superoxide production in macrophages. Both MIP-1 and BB-10010 enhanced monocyte migration, but cells were more sensitive to the native molecule, with optimal effects seen at 1 ng/mL versus 100 ng/mL. Neither has any observable proinflammatory effects on neutrophils in vitro (Williams et al., 1997). Based upon these promising in vitro results with BB-10010 (equivalent stem cell suppressor activity, diminished inflammatory cell chemoattractant, and activating activity) preclinical studies in animal models of chemotherapy-induced toxicity were initiated using this compound. MIP-1 has now been examined for its activity in alleviating the myelotoxicity associated with chemotherapeutic agents in several animal models. In mice MIP-1 was shown to reduce the extent of hematopoietic damage after repeated sublethal irradiations (Lord et al., 1995). MIP-1 has also been shown to enhance leukocyte recovery and progenitor cell mobilization after treatment (Lord et al., 1995). Other studies have shown BB-10010 to be myeloprotective at the stem cell level against the cytotoxic actions of S-phase active drugs such as hydroxyurea and cytosine arabinoside (Ara-C) (Gilmore et al., 1999). BB-10010 has also been examined for its effects on the proliferation of the small intestinal epithelium, which is particularly sensitive to radiation because it is such a rapidly dividing tissue. This latter study (Arango et al., 1999) demonstrated that BB-10010 acts to take intestinal cryptal cells out of the mitotic phase of the cell cycle, and therefore might prove to be a useful therapy to reduce the side-effects of radiation therapy in patients with abdominal or pelvic metastases.

Pharmacokinetics In one study the administration of BB-10010 (30± 300 mg/kg) as a single subcutaneous bolus produced sustained plasma concentrations over a 24 hour period. Plasma levels obtained with the 300 mg/kg dose equated to those required for in vivo activity, suggesting that a once daily injection is adequate for therapeutic use (Marshall et al., 1998).

Toxicity In an initial phase I study, BB-10010 had no apparent toxicity up to 300 mg/kg (Marshall et al., 1998), and in

all phase I and phase II studies carried out to date BB-10010 has been well tolerated (Bernstein et al., 1997; Broxmeyer et al., 1998; Clemons et al., 1998; Marshall et al., 1998). Treatment with BB-10010, even at the highest dose used, failed to elicit either a local or a systemic inflammatory response. A daily dose of > 30 mg/kg resulted in a dose-dependent monocytosis (Marshall et al., 1998).

Clinical results Based on the results obtained from preclinical studies in animals in which BB-10010 was found to be without apparent toxicity and to have stem cell protective properties, this molecule is now undergoing evaluation in humans. In a phase I clinical trial in cancer patients and normal healthy volunteers BB10010 was found to be well-tolerated. Treatment was associated with a dose-related monocytosis (Marshall et al., 1998). A second phase I clinical trial of BB10010 in patients with relapsed/refractory breast cancer demonstrated the suppressive and mobilizing effects of MIP-1 and BB-10010 previously noted in vivo in mice (Broxmeyer et al., 1998). In a first randomized phase II study of BB-10010 in patients receiving high dose etoposide and cyclophosphamide for malignant lymphoma and breast cancer the BB-10010 treatment regimin was again well tolerated, with no evidence of any effect of treatment on colony-forming cell or long-term culture initiating cell, but no beneficial effect on reducing the toxicity was observed. A second randomized phase II clinical trial of BB-10010 has been carried out in patients with locally advanced or metastatic breast cancer to evaluate the potential myeloprotective effects in patients undergoing a combination chemotherapy (5-fluorouracil, adriamycin, cyclophosphamide) regimen (Clemons et al., 1998). Again, BB-10010 was found to be well-tolerated in all patients. Although no statistically significant benefit was derived from BB10010 treatment in this study, there was some evidence to suggest a dose-dependent improvement in neutrophil recovery, and 50% of the BB-10010treated patients completed the trial with neutrophil counts higher than those in the control group, suggesting some myeloprotection against repeated cycles of combined chemotherapy. Alternative Therapeutic Strategies Designed to Antagonize MIP-1 and/or MIP-1 Actions The therapeutic strategies described above (BB-10010 as protective agent to protect against chemotherapyinduced toxicity; intracrines as reagents which

MIP-1, MIP-1 interfere with the trafficking of CCR5 to the plasma membrane thereby blocking HIV-1 entry into target cells) are designed to take advantage of the positive aspects of MIP-1 and/or MIP-1 biology. In addition to mediating activities like these which can be manipulated to benefit the host, MIP-1 and MIP1 have both been shown to mediate activities which contribute to the pathology associated with a number of disease states (e.g. sepsis, rheumatoid arthritis, multiple sclerosis). Therefore it is clear that in certain instances one could envision a therapeutic benefit from blocking the production and/or action of MIP1 and/or MIP-1 , or from interfering with MIP-1 and/or MIP-1 receptor interactions. Such strategies are discussed below. Therapies targeting MIP-1 and/or MIP-1 ligands directly: There have been several animal disease models in which the actions of endogenously produced MIP-1 and/or MIP-1 have been blocked by passive administration of neutralizing antibodies with resulting benefit to the host. The results of such studies are summarized in Table 11. In the case of MIP-1, the therapeutic utility of this type of approach (ligand elimination) has been confirmed by studies in which disease-related pathological complications have been compared in MIP-1 wildtype (‡/‡) versus MIP-1 knockout (ÿ/ÿ) mice and shown to be considerably reduced in several disease models (e.g. rheumatoid arthritis, EAE, GVHDassociated liver injury). This strategy (antibody neutralization of either MIP-1 or MIP-1 ), while promising, has not yet been tested clinically for any disease target. Therapies targeting MIP-1 and/or MIP-1 receptors: In addition to using MIP-1- and/or MIP-1 blocking strategies which involve targeting the ligand itself, one can envision blocking the pathologic actions of MIP-1 and/or MIP-1 by blocking their ability to bind to, and/or signal through, their cognate receptors. This can be achieved, for instance, by the use of peptide receptor antagonists or small molecule inhibitors that interfere with binding interactions between MIP-1 peptide receptors and their natural ligands. To date several peptide antagonists of MIP-1 and MIP-1 receptors (Met-RANTES, A.P.-RANTES, RANTES(6±68)) have been identified, and shown to block ligand binding to CCR1 and CCR5 (Proudfoot et al., 1999). The potential clinical utility of one of these, Met-RANTES, has already been demonstrated in several animal disease models including collagen-induced arthritis, necrotizing glomerulonephritis, and renal transplant rejection (Grone et al., 1999; Proudfoot et al., 1999). Because the receptors that recognize MIP-1 and MIP-1 (CCR1 and CCR5) are somewhat promiscuous, these peptide

1203

antagonists block the actions of multiple CC chemokines in vivo. For instance, Met-RANTES blocks the binding of RANTES, MCP-2, and MIP-1 to CCR1, and MIP-1, MIP-1 , and RANTES to CCR5 (Proudfoot et al., 1999). This may in part explain the effectiveness of these peptides as antiinflammatory agents in vivo, as they are capable of overcoming the inherent redundancy of the chemokine system. These peptide agents have not yet been tested clinically for any disease. Their discovery, use, and potential therapeutic modalities are discussed in greater detail in chapters reviewing CCR1 and CCR5 biology. Strategies targeting individual MIP-1 and/or MIP-1 receptors are more selective and may, under certain circumstances, provide a more controlled therapeutic benefit. The utility of such an approach has already been shown by studies in mice in which individual receptors are removed by targeted gene deletion (Locati and Murphy, 1999). To date, several small molecule inhibitors which interfere with the binding of MIP-1 and/or MIP-1 to their receptors have been identified (Hesselgesser et al., 1998; Baba et al., 1999). Members of a series of 4-hydroxypiperidine compounds were shown to potently and selectively antagonize MIP-1 (and RANTES) binding to, and signaling through, CCR1. The activity of these compounds to block MIP-1-mediated pathology in animal disease models has not yet been reported. A small molecule inhibitor of CCR5 has also been identified recently (Baba et al., 1999). The inhibitor, referred to as TAK-779, is a nonpeptide compound that antagonizes the binding of both MIP1 and MIP-1 to CCR5. The therapeutic utility of TAK-779 has been shown by its activity to inhibit the replication of R5 HIV-1 clinical isolates in peripheral blood mononuclear cells (Baba et al., 1999). The activity of this compound to block MIP-1- and/or MIP-1 -mediated pathology in animal disease models has not yet been assessed.

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