Macrophage-derived Chemokine

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Macrophage-derived Chemokine David Chantry and Patrick W. Gray* ICOS Corporation, 22021 20th Avenue SE, Bothell, WA 98021, USA * corresponding author tel: 425-485-1900, fax: 425-485-1961, e-mail: [email protected] DOI: 10.1006/rwcy.2001.11022.

SUMMARY

Alternative names

Macrophage-derived chemokine (MDC) is a member of the CC chemokine family. The receptor for MDC is CCR4, a G protein-coupled receptor expressed primarily on the TH2 subset of T lymphocytes and on developing T cells within the thymus. Consistent with this expression pattern, MDC is a chemoattractant for these cell types. MDC is also chemotactic for IL-2-activated NK cells, dendritic cells, and monocytes, although whether these effects are mediated through CCR4 or another, as yet to be identified receptor, is unclear. In vivo, MDC appears to be involved in the migration of developing T cells in the thymus, and of distinct subsets of mature T cells in the periphery. In the context of pathophysiology, MDC may play an important role in the migration of TH2 cells during allergic inflammation, and of CLA+ T cells to the skin in conditions such as psoriasis.

STCP-1 (stimulated T cell chemotactic protein), ABCD-1.

BACKGROUND

Main activities and pathophysiological roles

Discovery Macrophage-derived chemokine (MDC) was originally identified during the sequencing of randomly selected clones from human macrophages (Godiska et al., 1997; Chantry et al., 1998). A cDNA for the murine homolog of MDC was subsequently identified using suppression subtractive hybridization to identify transcripts which were upregulated following stimulation of pro-pre B cells with anti-CD40 and IL4 to mature S-" switched cells (Schaniel et al., 1998).

Cytokine Reference

Structure Only the primary sequence of MDC is known. MDC is a member of the CC family of chemokines and shares 28±35% amino acid identity with this group of proteins. This sequence conservation includes the four characteristic cysteines and nine other highly conserved residues (Chang et al., 1997; Godiska et al., 1997). At the C-terminus of MDC there is a stretch of basic residues which is also conserved within the chemokine family and which mediates their ability to interact with heparin.

MDC is chemotactic for a number of cell types, including thymocytes, monocytes, IL-2-activated NK cells, dendritic cells, and both TH2 and CLA+ T cells. In the context of pathophysiology the latter two activities are the most relevant. TH2 T cells are important mediators of allergic inflammation and MDC appears to play a role in the migration of this cell type in disease settings. MDC levels are elevated in the affected tissues in murine models of asthma (Gonzalo et al., 1999) and atopic dermatitis

Copyright # 2001 Academic Press

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David Chantry and Patrick W. Gray

(Vestergaard et al., 1999) and in the serum and tissue of humans with allergic inflammation (Galli et al., 2000). The CLA antigen is used to define those T cells which selectively home to skin. It has recently been shown that CLA+ T cells express CCR4 and will migrate in response to MDC (Campbell et al., 1999). MDC may therefore be involved in the migration of T cells to inflamed skin. Consistent with this, MDC and TARC (the other ligand for CCR4) have been shown to be expressed in human psoriatic skin (Campbell et al., 1999).

PROTEIN

GENE AND GENE REGULATION

Sequence

et al., 1998; Bonecchi et al., 1998), or by activation of B cells (Schaniel et al., 1998) or T cells (Galli et al., 2000).

Accession numbers Human: U83171 Mouse: AAD50547

Accession numbers

See Figure 1.

Human: U83171 Mouse: AF1632477 Rat: AF163476

Description of protein

Chromosome location 16q13

Regulatory sites and corresponding transcription factors No information is available. The genomic structure of MDC has been determined and the intron±exon boundaries are conserved between MDC and other members of the CC chemokine family. In addition the 30 untranslated region of the MDC cDNA is longer than that of other chemokines and includes three Alu repeats (Godiska et al., 1997).

Only the primary sequence of MDC is known. MDC is a member of the CC family of chemokines and shares 28±35% amino acid identity with this group of proteins, including four characteristic cysteines and nine other highly conserved residues. MDC is well conserved between species, mouse and rat MDC are 80% identical and share 65% identity with the human gene product (Chantry et al., 1999). At the Cterminus of MDC there is a stretch of basic residues which is also conserved both in MDC from different species and more broadly within the chemokine family and mediates interaction with heparin (Godiska et al., 1997).

Discussion of crystal structure Unknown. Structural information is only available by inference from other CC chemokines.

Important homologies Cells and tissues that express the gene MDC is expressed at high levels in thymus, lower levels of expression are seen in lymph node, appendix, small intestine and lung (Chang et al., 1997; Godiska et al., 1997). Expression of the MDC mRNA is upregulated during the differentiation of monocytes to macrophages (Godiska et al., 1997) and Langerhans cells to dendritic cells (Tang and Cyster, 1999). MDC expression can also be induced in monocytes by treatment with IL-4 or IL-13 (Andrew

MDC is most closely related to the CC chemokine TARC. TARC appears to be regulated in a manner Figure 1 MDC.

Amino acid sequence for human and mouse

Macrophage-derived Chemokine 3 similar to MDC, it is a ligand for CCR4 and maps near MDC on chromosome 16q13 (Imai et al., 1998).

Posttranslational modifications MDC has been expressed and purifed from mammalian cells and does not appear to be glycosylated (Godiska et al., 1997). MDC is processed by removal of a 24 amino acid leader sequence to generate the mature, biologically active protein. There is evidence that MDC might undergo additional proteolytic processing, it is a substrate in vitro for the dipeptidylpeptidase CD26 (Struyf et al., 1999; Proost et al., 1999), but the in vivo significance of this observation is unclear.

CELLULAR SOURCES AND TISSUE EXPRESSION

Cellular sources that produce In vitro, MDC can be made by monocytes, macrophages, dendritic cells, B cells, and T cells.

Eliciting and inhibitory stimuli, including exogenous and endogenous modulators Expression of MDC can be induced by a number of different stimuli. In monocytes MDC expression is induced by IL-4, IL-13, and GM-CSF (Andrew et al., 1998; Bonecchi et al., 1998). Activation of T cells with antibodies to CD3 and CD28, or by using calcium ionophore and phorbol ester, elicit MDC production (Galli et al., 2000), while B cells and dendritic cells can be stimulated to produce MDC by activation with CD40L (Schaniel et al., 1998). MDC is also made constitutively by differentiated human macrophages (Godiska et al., 1997), and dendritic cells (Godiska et al., 1997; Tang and Cyster, 1999). The induction of MDC expression in human monocytes by IL-4 or IL-13 is inhibited by IFN (Andrew et al., 1998; Bonecchi et al., 1998).

RECEPTOR UTILIZATION MDC is a ligand for the receptor CCR4 which is a member of the G protein-coupled receptor

superfamily (Imai et al., 1998). It has been suggested that additional receptor(s) for MDC may be expressed on human monocytes (Struyf et al., 1999; Proost et al., 1999) and eosinophils (Bochner et al., 1999) and murine TH1 cells (Schaniel et al., 1999). As yet these receptors have not been identified at the molecular level.

IN VITRO ACTIVITIES

In vitro findings In vitro, MDC is chemotactic for a number of cell types including thymocytes (Cambell et al., 1999; Chantry et al., 1999), dendritic cells, monocytes, IL-2activated NK cells (Godiska et al., 1997), TH2 T cells (Bonecchi et al., 1998; Sallusto et al., 1998; Imai et al., 1998) and CLA+ T cells (Cambell et al., 1999). MDC has also been reported to inhibit HIV replication in vitro (Pal et al., 1997; Struyf et al., 1999), although the physiological significance of this observation is still unclear.

Regulatory molecules: Inhibitors and enhancers Monocyte expression of MDC is inhibited by IFN (Andrew et al., 1998; Bonecchi et al., 1998).

Bioassays used MDC biological activity is assayed by calcium flux or chemotaxis using either primary cells or more commonly stable transfectants expressing CCR4 (Imai et al., 1998).

IN VIVO BIOLOGICAL ACTIVITIES OF LIGANDS IN ANIMAL MODELS

Normal physiological roles In normal tissues, MDC mRNA is expressed at highest levels in thymus (Godiska et al., 1997). Immunocytochemistry has been used to localize MDC expression within the thymus to the medulla (Chantry et al., 1999) and MDC has been shown to be

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David Chantry and Patrick W. Gray

chemotactic for thymocytes (Chantry et al., 1999; Campbell et al., 1999). These findings suggest that MDC may play a role in the migration of developing T cells from the cortex to the medulla. There is also evidence that MDC may be involved in the migration of T cells during an immune response. Following antigenic challenge in the skin Langerhans cells take up antigen, migrate to draining lymph nodes, undergo a program of differentiation to dendritic cells and present antigen to T cells. MDC is not expressed by nave Langerhans cells, but as differentiation to the dendritic cells takes place, MDC expression is dramatically upregulated (Tang and Cyster, 1999). These findings suggest that MDC may be involved in the colocalization of T cells and dendritic cells within the lymph node during the generation of an immune response (Kanazawa et al., 1999; Tang and Cyster, 1999).

Species differences MDC is well conserved between species; mouse and human MDC are 65% identical at the amino acid level (Chantry et al., 1999), and murine MDC will signal through human CCR4. In addition, the in vivo expression pattern of MDC appears to be similar in humans and rodents (Chang et al., 1997; Godiska et al., 1997; Chantry et al., 1999).

Interactions with cytokine network The induction of MDC expression in human monocytes by IL-4 or IL-13 is inhibited by IFN (Bonecchi et al., 1998).

Endogenous inhibitors and enhancers Little is known about the in vivo regulation of MDC function. In vitro studies have shown that MDC is a substrate for the dipeptidylpeptidase CD26, which removes the first two or four amino acids from the mature form of MDC (Struyf et al., 1999). MDC which is modified in this fashion will no longer interact with CCR4 and is no longer chemotactic for T lymphocytes (Proost et al., 1999). However these truncated forms of MDC retain their ability to stimulate monocyte chemotaxis and to inhibit HIV replication in vitro, suggesting that additional receptors for MDC may exist (Proost et al., 1999; Struyf et al., 1999).

PATHOPHYSIOLOGICAL ROLES IN NORMAL HUMANS AND DISEASE STATES AND DIAGNOSTIC UTILITY

Normal levels and effects MDC is present in serum of normal individuals (200± 1000 pg/mL) (Galli et al., 2000), but the physiological significance of this is unknown. Immunocytochemistry has also revealed expression of MDC protein in the thymus, where it may play a role in the migration of developing T cells (Chantry et al., 1999).

Role in experiments of nature and disease states MDC levels are significantly elevated in the serum of patients with diseases characterized by the activation of TH2 T cells and this is associated with local expression of MDC at disease sites (Galli et al., 2000). MDC expression has also been found to be elevated in a murine model of asthma (Gonzalo et al., 1999) and in a spontaneous mouse model of atopic dermatitis (Vestergaard et al., 1999).

IN THERAPY

Effects of therapy: Cytokine, antibody to cytokine inhibitors, etc. Neutralizing antibodies to MDC have been shown to block airway hyperreactivity in a murine model of asthma (Gonzalo et al., 1999).

References Andrew, D. P., Chang, M.-S., McNinch, J., Wathen, S. T., Rihank, M., Tseng, J., Spellberg, J. P., and Elias, G.E. III. (1998). STCP-1 (MDC) CC chemokine acts specifically on chronically activated TH2 lymphocytes and is produced by monocytes on stimulation with TH2 cytokines IL-4 and IL-13. J. Immunol. 161, 5027±5038. Bochner, B. S., Bickel, C. A., Taylor, M. L., MacGlashan, D.W. Jr, Gray, P. W., Raport, C. J., and Godiska, R. (1999). Macrophagederived chemokine induces human eosinophil chemotaxis in a CC chemokine receptor 3- and CC chemokine receptor 4-independent manner. J. Allergy Clin. Immunol. 103, 527±532. Bonecchi, R., Sozzani, S., Stine, J. T., Luini, W., D'Amico, G., Allavena, P., Chantry, D., and Mantovani, A. (1998). Divergent

Macrophage-derived Chemokine 5 effects of interleukin-4 and interferon- on macrophage-derived chemokine (MDC) production: an amplification circuit of polarized T helper 2 response. Blood 92, 2668±2671. Campbell, J. J., Haraldsen, G., Pan, J., Rottman, J., Qin, S., Ponath, P., Andrew, D. P., Warnke, R., Ruffing, N., Kassam, N., Wu, L., and Butcher, E. C. (1999). The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells. Nature 400, 776±780. Chang, M. S., McNinch, J., Elias, C. 3rd, Manthey, C. L., Grosshans, D., Meng, T., Boone, T., and Andrew, D. P. (1997). Molecular cloning and functional characterization of a novel CC chemokine, stimulated T cell chemotactic protein (STCP-1) that specifically acts on activated T lymphocytes. J. Biol. Chem. 272, 25229±25237. Chantry, D., DeMaggio, A. J., Brammer, H., Raport, C. J., Wood, C. L., Schweickart, V. L., Epp, A., Smith, A., Stine, J. T., Walton, K., Tjoelker, Godiska, R., and Gray, P. W. (1998). Profile of human macrophage transcripts: insights into macrophage biology and identification of novel chemokines. J. Leukoc. Biol. 64, 49±54. Chantry, D., Romagnani, P., Raport, C. J., Wood, C. L., Epp, A., Romagnani, S., and Gray, P. W. (1999). Macrophage derived chemokine (MDC) is localized to thymic medullary epithelial cells and is a chemoattractant for CD3+, CD4+, CD8low thymocytes. Blood 94, 1890±1898. Galli, G., Chantry, D., Annunziato, F., Romagnani, P., Cosmi, L., Lazzeri, E., Manetti, R., Maggi, E., Gray, P. W., and Romagnani, S. (2000). MDC production by human TH2 cells in vitro and in vivo. Eur. J. Immunol. 30, 204±210. Godiska R., Chantry, D., Raport, C. J., Sozzani, S., Allavena, Mantovani, A., and Gray, P. W. (1997). Human Macrophage Derived Chemokine (MDC), a novel chemoattractant for dendritic and natural killer cells. J. Exp. Med. 185, 1595±1604. Gonzalo, J.-A., Pan, Y., Lloyd, C. M., Jia, G.-Q., Yu, G., Dussault, B., Powers, C. A., Proudfoot, A.E. I., Coyle, A. J., Gearing, D., and Gutierrez-Ramos, J.-C. (1999). Mouse moncoyte derived chemokine is involved in airway hyperactivity and lung inflammation. J. Immunol. 163, 403±411. Imai, T., Chantry, D., Raport, C. J., Wood, C., Nishimura, M., Godiska, R., Yoshie, Y., and Gray, P. W. (1998). Macrophage derived chemokine is a functional ligand for the CC chemokine receptor CCR4. J. Biol. Chem. 273, 1764±1770. Kanazawa, N., Nakamura, T., Tashiro, K., Muramatsu, M., Moritta, K., Yoneda, K., Inaba, K., Imamura, S., and Honjo, T. (1999). Fractalkine and macrophage-derived chemokine: T cell-attracting chemokines expressed in T cell area dendritic cells. Eur. J. Immunol. 29, 1925±1932.

Pal, R., Garzino-Demo, A., Markham, P. D., Burns, J., Brown, M., Gallo, R. C., and DeVico, A. L. (1997). Inhibition of HIV-1 infection by the b-chemokine MDC. Science 278, 695±698. Proost, P., Struyf, S., Schols, D., Opdenakker, G., Sozzani, S., Allavena, P., Mantovani, A., Augustyns, K., Bal, G., Haemers, A., Lambeir, A.-M., Scharpe, S., Van Damme, J., and De Meester, I. (1999). Truncation of macrophage-derived chemokine by CD26/dipeptidyl-peptidase IV beyond it's predicted cleavage site affects chemotactic activity and CC chemokine receptor 4 interactions. J. Biol. Chem. 274, 3988±3993. Sallusto, F., Lenig, D., Mackay, C. R., and Lanzavecchia, A. (1998). Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. J. Exp. Med. 187, 875±883. Schaniel, C., Pardali, E., Sallustu, F., Speletas, M., Ruedl, C., Shimizu, T., Seidl, T., Anderrson, J., Melchers, F., Rolink, A. G., and Sideras, P. (1998). Activated murine B lymphocytes and dendritic cells produce a novel CC chemokine which acts selectively on activated T cells. J. Exp. Med. 188, 451±463. Schaniel, C., Sallusto, F., Ruedl, C., Sideras, P., Melchers, F., and Rolink, A. G. (1999). Three chemokines with potential functions in T lymphocyte-independent and -dependent B lymphocyte stimulation. Eur. J. Immunol. 29, 2934±2947. Struyf, S., Proost, P., Sozzani, S., Mantovani, A., Wuyts, A., De Clerq, E., Schols, D., and Van Damme, J. (1999). Enhanced anti-HIV activity and altered chemotactic potency of NH2terminally processed Macrophage-derived chemokine (MDC) imply an additional MDC receptor. J. Immunol. 161, 2672±2675. Tang, H. L., and Cyster, J. G. (1999). Chemokine up-regulation and activated T cell attraction by maturing dendritic cells. Science 284, 819±822. Vestergaard, C., Yoneyama, H., Murai, M., Nakamura, K., Tamaki, K., Terashima, Y., Imai, T., Yoshie, O., Irimura, T., Mizutani, H., and Matsushima, K. (1999). Overproduction of Th2-specific chemokines in NC/Nga mice exhibiting atopic dermatitis-like lesions. J. Clin. Invest. 104, 1097±1105.

LICENSED PRODUCTS R & D Systems: Recombinant mouse and human MDC. Peprotech: Recombinant mouse and human MDC.