IL-17 Receptor

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IL-17 Receptor Serge Lebecque*, FrancËois Fossiez and Elizabeth Bates Laboratory for Immunological Research, Schering-Plough, 27 Chemin des Peupliers, Dardilly, 69572, France * corresponding author tel: (33) 4 72 17 27 00, fax: (33) 4 78 35 47 50, e-mail: [email protected] DOI: 10.1006/rwcy.2000.14010.

SUMMARY

GENE

A ubiquitously expressed, large (864 aa) mouse membrane glycoprotein has been cloned after its binding to soluble vIL-17±Fc fusion protein. This receptor, which also binds CTLA-8, is unrelated to previously identified cytokine receptor families. The cDNA encoding a human homolog of the mIL-17R has been isolated by crosshybridization. Like its mouse counterpart, the human IL-17R (866 aa) is also ubiquitously expressed. Monoclonal antibodies against the hIL-17R block the secretion by fibroblasts of IL-6 induced by hIL-17±Fc. Binding studies, dose± response, and cellular restriction of IL-17 biological activities suggest the existence of another, as yet unidentified, high-affinity IL-17R chain.

Accession numbers

BACKGROUND

Discovery A mouse cDNA encoding an IL-17-binding protein has been cloned using a chimeric protein comprising a portion of the Fc region of human IgG1 followed by amino acids 19±151 of vIL-17 (Yao et al., 1995a). The vIL-17±Fc fusion protein specifically bound the murine thymoma cell line EL4, from which a cDNA library was screened to isolate the gene encoding the binding molecule. When expressed in mammalian cells, the putative IL-17 receptor was shown to bind vIL-17 as well as mIL-17±Fc fusion proteins. Using the mouse cDNA as a probe, the human homolog was cloned from a human T cell library (Yao et al., 1997).

Human IL-17R mRNA: U58917 Mouse IL-17R mRNA: U31993

Sequence See Figure 1.

Chromosome location and linkages The chromosomal localization of IL-17R is not homologous between mouse (chromosome 6, between Raf1 and CD4, in the vicinity of the recently described macrophage-restricted group II C-type lectin mcl gene locus (Yao et al., 1995b; Balch et al., 1998) and human (chromosome 22, between markers F8VWFP and D22S420) (Yao et al., 1997).

PROTEIN

Accession numbers Human IL-17R: U58917 Mouse IL-17R: U31993

Sequence See Figure 2.

1542 Serge Lebecque, FrancËois Fossiez and Elizabeth Bates Figure 1 Human and mouse IL-17R mRNA nucleotide sequences. Start codon is in bold; stop codon is underlined. Human IL-17R mRNA GGGGCCGAGCCCTCCGCGACGCCACCCGGGCCATGGGGGCCGCACGCAGCCCGCCGTCCGCTGTCCCGGGGCCCCTGCTGGGGCTGCTCCTGCTGCT CCTGGGCGTGCTGGCCCCGGGTGGCGCCTCCCTGCGACTCCTGGACCACCGGGCGCTGGTCTGCTCCCAGCCGGGGCTAAACTGCACGGTCAAGAAT AGTACCTGCCTGGATGACAGCTGGATTCACCCTCGAAACCTGACCCCCTCCTCCCCAAAGGACCTGCAGATCCAGCTGCACTTTGCCCACACCCAAC AAGGAGACCTGTTCCCCGTGGCTCACATCGAATGGACACTGCAGACAGACGCCAGCATCCTGTACCTCGAGGGTGCAGAGTTATCTGTCCTGCAGCT GAACACCAATGAACGTTTGTGCGTCAGGTTTGAGTTTCTGTCCAAACTGAGGCATCACCACAGGCGGTGGCGTTTTACCTTCAGCCACTTTGTGGTT GACCCTGACCAGGAATATGAGGTGACCGTTCACCACCTGCCCAAGCCCATCCCTGATGGGGACCCAAACCACCAGTCCAAGAATTTCCTTGTGCCTG ACTGTGAGCACGCCAGGATGAAGGTAACCACGCCATGCATGAGCTCAGGCAGCCTGTGGGACCCCAACATCACCGTGGAGACCCTGGAGGCCCACCA GCTGCGTGTGAGCTTCACCCTGTGGAACGAATCTACCCATTACCAGATCCTGCTGACCAGTTTTCCGCACATGGAGAACCACAGTTGCTTTGAGCAC ATGCACCACATACCTGCGCCCAGACCAGAAGAGTTCCACCAGCGATCCAACGTCACACTCACTCTACGCAACCTTAAAGGGTGCTGTCGCCACCAAG TGCAGATCCAGCCCTTCTTCAGCAGCTGCCTCAATGACTGCCTCAGACACTCCGCGACTGTTTCCTGCCCAGAAATGCCAGACACTCCAGAACCAAT TCCGGACTACATGCCCCTGTGGGTGTACTGGTTCATCACGGGCATCTCCATCCTGCTGGTGGGCTCCGTCATCCTGCTCATCGTCTGCATGACCTGG AGGCTAGCTGGGCCTGGAAGTGAAAAATACAGTGATGACACCAAATACACCGATGGCCTGCCTGCGGCTGACCTGATCCCCCCACCGCTGAAGCCCA GGAAGGTCTGGATCATCTACTCAGCCGACCACCCCCTCTACGTGGACGTGGTCCTGAAATTCGCCCAGTTCCTGCTCACCGCCTGCGGCACGGAAGT GGCCCTGGACCTGCTGGAAGAGCAGGCCATCTCGGAGGCAGGAGTCATGACCTGGGTGGGCCGTCAGAAGCAGGAGATGGTGGAGAGCAACTCTAAG ATCATCGTCCTGTGCTCCCGCGGCACGCGCGCCAAGTGGCAGGCGCTCCTGGGCCGGGGGGCGCCTGTGCGGCTGCGCTGCGACCACGGAAAGCCCG TGGGGGACCTGTTCACTGCAGCCATGAACATGATCCTCCCGGACTTCAAGAGGCCAGCCTGCTTCGGCACCTACGTAGTCTGCTACTTCAGCGAGGT CAGCTGTGACGGCGACGTCCCCGACCTGTTCGGCGCGGCGCCGCGGTACCCGCTCATGGACAGGTTCGAGGAGGTGTACTTCCGCATCCAGGACCTG GAGATGTTCCAGCCGGGCCGCATGCACCGCGTAGGGGAGCTGTCGGGGGACAACTACCTGCGGAGCCCGGGCGGCAGGCAGCTCCGCGCCGCCCTGG ACAGGTTCCGGGACTGGCAGGTCCGCTGTCCCGACTGGTTCGAATGTGAGAACCTCTACTCAGCAGATGACCAGGATGCCCCGTCCCTGGACGAAGA GGTGTTTGAGGAGCCACTGCTGCCTCCGGGAACCGGCATCGTGAAGCGGGCGCCCCTGGTGCGCGAGCCTGGCTCCCAGGCCTGCCTGGCCATAGAC CCGCTGGTCGGGGAGGAAGGAGGAGCAGCAGTGGCAAAGCTGGAACCTCACCTGCAGCCCCGGGGTCAGCCAGCGCCGCAGCCCCTCCACACCCTGG TGCTCGCCGCAGAGGAGGGGGCCCTGGTGGCCGCGGTGGAGCCTGGGCCCCTGGCTGACGGTGCCGCAGTCCGGCTGGCACTGGCGGGGGAGGGCGA GGCCTGCCCGCTGCTGGGCAGCCCGGGCGCTGGGCGAAATAGCGTCCTCTTCCTCCCCGTGGACCCCGAGGACTCGCCCCTTGGCAGCAGCACCCCC ATGGCGTCTCCTGACCTCCTTCCAGAGGACGTGAGGGAGCACCTCGAAGGCTTGATGCTCTCGCTCTTCGAGCAGAGTCTGAGCTGCCAGGCCCAGG GGGGCTGCAGTAGACCCGCCATGGTCCTCACAGACCCACACACGCCCTACGAGGAGGAGCAGCGGCAGTCAGTGCAGTCTGACCAGGGCTACATCTC CAGGAGCTCCCCGCAGCCCCCCGAGGGACTCACGGAAATGGAGGAAGAGGAGGAAGAGGAGCAGGACCCAGGGAAGCCGGCCCTGCCACTCTCTCCC GAGGACCTGGAGAGCCTGAGGAGCCTCCAGCGGCAGCTGCTTTTCCGCCAGCTGCAGAAGAACTCGGGCTGGGACACGATGGGGTCAGAGTCAGAGG GGCCCAGTGCATGAGGGCGGCTCCCCAGGGACCGCCCAGATCCCAGCTTTGAGAGAGGAGTGTGTGTGCACGTATTCATCTGTGTGTACATGTCTGC ATGTGTATATGTTCGTGTGTGAAATGTAGGCTTTAAAATGTAAATGTCTGGATTTTAATCCCAGGCATCCCTCCTAACTTTTCTTTGTGCAGCGGTC TGGTTATCGTCTATCCCCAGGGGAATCCACACAGCCCGCTCCCAGGAGCTAATGGTAGAGCGTCCTTGAGGCTCCATTATTCGTTCATTCAGCATTT ATTGTGCACCTACTATGTGGCGGGCATTTGGGATACCAAGATAAATTGCATGCGGCATGGCCCCAGCCATGAAGGAACTTAACCGCTAGTGCCGAGG ACACGTTAAACGAACAGGATGGGCCGGGCACGGTGGCTCACGCCTGTAATCCCAGCACACTGGGAGGCCGAGGCAGGTGGATCACTCTGAGGTCAGG AGTTTGAGCCAGCCTG Mouse IL-17R mRNA GTCGACTGGAACGAGACGACCTGCTGCCGACGAGCGCCAGTCCTCGGCCGGGAAAGCCATCGCGGGCCCTCGCTGTCGCGCGGAGCCAGCTGCGAGC GCTCCGCGACCGGGCCGAGGGCTATGGCGATTCGGCGCTGCTGGCCACGGGTCGTCCCCGGGCCCGCGCTGGGATGGCTGCTTCTGCTGCTGAACGT TCTGGCCCCGGGCCGCGCCTCCCCGCGCCTCCTCGACTTCCCGGCTCCGGTCTGCGCGCAGGAGGGGCTGAGCTGCAGAGTCAAGAATAGTACTTGT CTGGATGACAGCTGGATCCACCCCAAAAACCTGACCCCGTCTTCCCCAAAAAACATCTATATCAATCTTAGTGTTTCCTCTACCCAGCACGGAGAAT TAGTCCCTGTGTTGCATGTTGAGTGGACCCTGCAGACAGATGCCAGCATCCTGTACCTCGAGGGTGCAGAGCTGTCCGTCCTGCAGCTGAACACCAA TGAGCGGCTGTGTGTCAAGTTCCAGTTTCTGTCCATGCTGCAGCATCACCGTAAGCGGTGGCGGTTTTCCTTCAGCCACTTTGTGGTAGATCCTGGC CAGGAGTATGAAGTGACTGTTCACCACCTGCCGAAGCCCATCCCTGATGGGGACCCAAACCACAAATCCAAGATCATCTTTGTGCCTGACTGTGAGG ACAGCAAGATGAAGATGACTACCTCATGCGTGAGCTCAGGCAGCCTTTGGGATCCCAACATCACTGTGGAGACCTTGGACACACAGCATCTGCGAGT GGACTTCACCCTGTGGAATGAATCCACCCCCTACCAGGTCCTGCTGGAAAGTTTCTCCGACTCAGAGAACCACAGCTGCTTTGATGTCGTTAAACAA ATATTTGCGCCCAGGCAAGAAGAATTCCATCAGCGAGCTAATGTCACATTCACTCTAAGCAAGTTTCACTGGTGCTGCCATCACCACGTGCAGGTCC AGCCCTTCTTCAGCAGCTGCCTAAATGACTGTTTGAGACACGCTGTGACTGTGCCCTGCCCAGTAATCTCAAATACCACAGTTCCCAAGCCAGTTGC AGACTACATTCCCCTGTGGGTGTATGGCCTCATCACACTCATCGCCATTCTGCTGGTGGGATCTGTCATCGTGCTGATCATCTGTATGACCTGGAGG CTTTCTGGCGCCGATCAAGAGAAACATGGTGATGACTCCAAAATCAATGGCATCTTGCCCGTAGCAGACCTGACTCCCCCACCCCTGAGGCCCAGGA AGGTCTGGATCGTCTACTCGGCCGACCACCCCCTCTATGTGGAGGTGGTCCTAAAGTTCGCCCAGTTCCTGATCACTGCCTGTGGCACTGAAGTAGC CCTTGACCTCCTGGAAGAGCAGGTTATCTCTGAGGTGGGGGTCATGACCTGGGTGAGCCGACAGAAGCAGGAGATGGTGGAGAGCAACTCCAAAATC ATCATCCTGTGTTCCCGAGGCACCCAAGCAAAGTGGAAAGCTATCTTGGGTTGGGCTGAGCCTGCTGTCCAGCTACGGTGTGACCACTGGAAGCCTG CTGGGGACCTTTTCACTGCAGCCATGAACATGATCCTGCCAGACTTCAAGAGGCCAGCCTGCTTCGGCACCTACGTTGTTTGCTACTTCAGTGGCAT CTGTAGTGAGAGGGATGTCCCCGACCTCTTCAACATCACCTCCAGGTACCCACTCATGGACAGATTTGAGGAGGTTTACTTCCGGATCCAGGACCTG GAGATGTTTGAACCCGGCCGGATGCACCATGTCAGAGAGCTCACAGGGGACAATTACCTGCAGAGCCCTAGTGGCCGGCAGCTCAAGGAGGCTGTGC TTAGGTTCCAGGAGTGGCAAACCCAGTGCCCCGACTGGTTCGAGCGTGAGAACCTCTGCTTAGCTGATGGCCAAGATCTTCCCTCCCTGGATGAAGA AGTGTTTGAAGACCCACTGCTGCCACCAGGGGGAGGAATTGTCAAACAGCAGCCCCTGGTGCGGGAACTCCCATCTGACGGCTGCCTTGTGGTAGAT GTCTGTGTCAGTGAGGAAGAAAGTAGAATGGCAAAGCTGGACCCTCAGCTATGGCCACAGAGAGAGCTAGTGGCTCACACCCTCCAAAGCATGGTGC TGCCAGCAGAGCAGGTCCCTGCAGCTCATGTGGTGGAGCCTCTCCATCTCCCAGACGGCAGTGGAGCAGCTGCCCAGCTGCCCATGACAGAGGACAG CGAGGCTTGCCCGCTGCTGGGGGTCCAGAGGAACAGCATCCTTTGCCTCCCCGTGGACTCAGATGACTTGCCACTCTGTAGCACCCCAATGATGTCA CCTGACCACCTCCAAGGCGATGCAAGAGAGCAGCTAGAAAGCCTAATGCTCTCGGTGCTGCAGCAGAGCCTGAGTGGACAGCCCCTGGAGAGCTGGC CGAGGCCAGAGGTGGTCCTCGAGGGCTGCACACCCTCTGAGGAGGAGCAGCGGCAGTCGGTGCAGTCGGACCAGGGCTACATCTCCAGGAGCTCCCC GCAGCCCCCCGAGTGGCTCACGGAGGAGGAAGAGCTAGAACTGGGTGAGCCCGTTGAGTCTCTCTCTCCTGAGGAACTACGGAGCCTGAGGAAGCTC CAGAGGCAGCTTTTCTTCTGGGAGCTCGAGAAGAACCCTGGCTGGAACAGCTTGGAGCCACGGAGACCCACCCCAGAAGAGCAGAATCCCTCCTAGG CCTCCTGAGCCTGCTACTTAAGAGGGTGTATATTGTACTCTGTGTGTGCGTGCGTGTGTGTGTGTGTGTGTGTGTGTGTGTGCGTGTGTGTGTGTGT GTGTGTGTGTGTGTGTGTGTAGTGCCCGGCTTAGAAATGTGAACATCTGAATCTGACATAGTGTTGTATACCTGAAGTCCCAGCACTTGGGAACTGA GACTTGATGATCTCCTGAAGCCAGGTGTTCAGGGCCAGTGTGAAAACATAGCAAGACCTCAGAGAAATCAATGCAGACATCTTGGTACTGATCCCTA AACACACCCCTTTCCCTGATAACCCGACATGAGCATCTGGTCATCATTGCACAAGAATCCACAGCCCGTTCCCAGAGCTCATAGCCAAGTGTGTTGC TCATTCCTTGAATATTTATTCTGTACCTACTATTCATCAGACATTTGGAATTCAAAAACAAGTTACATGACACAGCCTTAGCCACTAAGAAGCTTAA AATTCGGTAAGGATGTAAAATTAGCCAGGATGAATAGAGGGCTGCTGCCCTGGCTGCAGAAGAGCAGGTCGTCTCGTTCCAGTCGAC

IL-17 Receptor 1543 Figure 2 Amino acid sequences for human and mouse IL-17R. Human IL-17R MGAARSPPSA VPGPLLGLLL TVKNSTCLDD SWIHPRNLTP QTDASILYLE GAELSVLQLN VDPDQEYEVT VHHLPKPIPD SLWDPNITVE TLEAHQLRVS HIPAPRPEEF HQRSNVTLTL VSCPEMPDTP EPIPDYMPLW GSEKYSDDTK YTDGLPAADL FLLTACGTEV ALDLLEEQAI TRAKWQALLG RGAPVRLRCD VCYFSEVSCD GDVPDLFGAA GELSGDNYLR SPGGRQLRAA LDEEVFEEPL LPPGTGIVKR EPHLQPRGQP APQPLHTLVL EACPLLGSPG AGRNSVLFLP LMLSLFEQSL SCQAQGGCSR SPQPPEGLTE MEEEEEEEQD NSGWDTMGSE SEGPSA Mouse IL-17R MAIRRCWPRV VPGPALGWLL RVKNSTCLDD SWIHPKNLTP QTDASILYLE GAELSVLQLN VDPGQEYEVT VHHLPKPIPD SLWDPNITVE TLDTQHLRVD QIFAPRQEEF HQRANVTFTL VPCPVISNTT VPKPVADYIP GADQEKHGDD SKINGILPVA AQFLITACGT EVALDLLEEQ RGTQAKWKAI LGWAEPAVQL TYVVCYFSGI CSERDVPDLF HHVRELTGDN YLQSPSGRQL LPSLDEEVFE DPLLPPGGGI KLDPQLWPQR ELVAHTLQSM TEDSEACPLL GVQRNSILCL LMLSVLQQSL SGQPLESWPR PQPPEWLTEE EELELGEPVE LEPRRPTPEE QNPS

LLLGVLAPGG SSPKDLQIQL TNERLCVRFE GDPNHQSKNF FTLWNESTHY RNLKGCCRHQ VYWFITGISI IPPPLKPRKV SEAGVMTWVG HGKPVGDLFT PRYPLMDRFE LDRFRDWQVR APLVREPGSQ AAEEGALVAA VDPEDSPLGS PAMVLTDPHT PGKPALPLSP

LLLNVLAPGR SSPKNIYINL TNERLCVKFQ GDPNHKSKII FTLWNESTPY SKFHWCCHHH LWVYGLITLI DLTPPPLRPR VISEVGVMTW RCDHWKPAGD NITSRYPLMD KEAVLRFQEW VKQQPLVREL VLPAEQVPAA PVDSDDLPLC PEVVLEGCTP SLSPEELRSL

ASLRLLDHRA HFAHTQQGDL FLSKLRHHHR LVPDCEHARM QILLTSFPHM VQIQPFFSSC LLVGSVILLI WIIYSADHPL RQKQEMVESN AAMNMILPDF EVYFRIQDLE CPDWFECENL ACLAIDPLVG VEPGPLADGA STPMASPDLL PYEEEQRQSV EDLESLRSLQ

ASPRLLDFPA SVSSTQHGEL FLSMLQHHRK FVPDCEDSKM QVLLESFSDS VQVQPFFSSC AILLVGSVIV KVWIVYSADH VSRQKQEMVE LFTAAMNMIL RFEEVYFRIQ QTQCPDWFER PSDGCLVVDV HVVEPLHLPD STPMMSPDHL SEEEQRQSVQ RKLQRQLFFW

LVCSQPGLNC FPVAHIEWTL RWRFTFSHFV KVTTPCMSSG ENHSCFEHMH LNDCLRHSAT VCMTWRLAGP YVDVVLKFAQ SKIIVLCSRG KRPACFGTYV MFQPGRMHRV YSADDQDAPS EEGGAAVAKL AVRLALAGEG PEDVREHLEG QSDQGYISRS RQLLFRQLQK

PVCAQEGLSC VPVLHVEWTL RWRFSFSHFV KMTTSCVSSG ENHSCFDVVK LNDCLRHAVT LIICMTWRLS PLYVEVVLKF SNSKIIILCS PDFKRPACFG DLEMFEPGRM ENLCLADGQD CVSEEESRMA GSGAAAQLPM QGDAREQLES SDQGYISRSS ELEKNPGWNS

Description of protein The predicted human receptor is a type I membrane glycoprotein with a 293 amino acid extracellular domain, a 21 amino acid transmembrane region, and 525 amino acid cytoplasmic tail. Human and mouse IL-17 receptors appear highly conserved as they share 82% amino acid similarity and 69% identity, and six potential N-linked glycosylation sites. Comparison of both human and mouse IL-17R sequences with public databases revealed no significant homology with known nucleotide and protein sequences. IL-17R does not include structural features of the immunoglobulin superfamily nor of the TNF receptor family. The extracellular domain does not contain the WSXWS motif found in hematopoietin receptor family members (Cosman, 1993). However, a relatively large proportion of acidic (16%) and proline (9%) residues is shared with other growth factor receptors, and a segment (TPPPLRPRKVW) located

close to the mIL-17R transmembrane domain is highly conserved among cytokine receptors. While no homology with tyrosine kinase catalytic domains could be found in the large cytoplasmic tail, two acidic regions and a serine-rich region are also present in the IL-2R chain, the IL-4R, and the G-CSFR. The molecular mass of the molecule immunoprecipitated using the m202 anti-hIL-17R antibody is larger (128±132 kDa) than predicted from the hIL-17R cDNA sequence. Expression of hIL-17R in the presence of tunicamycin demonstrated that the Nlinked glycosylation sites of the extracellular domain are indeed utilized.

Affinity for ligand(s) Direct binding assays revealed a relatively weak affinity for hIL-17 (Ka values in the range of 2  107 to 2  108), which was unexpected from the low concentrations of IL-17 needed for most half-maximal biological activities (between 2 and 50 ng/mL). This discrepancy suggests that an as yet unidentified high-affinity converting subunit might be present on IL-17-responsive cells (Yao et al., 1997).

Cell types and tissues expressing the receptor Human IL-17R mRNA is constitutively and widely expressed, as it was detected by PCR in total PBMCs, in NK cells, in Raji B cell line, in myelomonocytic THP1 cell line, in lung epithelial cell lines, and in the embryonal kidney line 293. Cell surface expression was confirmed by flow cytometric analysis using hIL17±Fc (Yao et al., 1997). Likewise, analysis by northern blot of the tissue distribution of mIL-17R showed that a single band of approximatively 3.7 kb is present in all tested tissues, with strong signals observed in spleen and kidney. Moderate signals are observed in lung and liver, and weaker signals in brain, testes, heart and skeletal muscles. Likewise, northern blot and RT-PCR detected the mIL-17R mRNA in every cell line tested (including fetal liver epithelial cells, rat intestinal epithelial cells, fibroblasts, muscle cells, mast cells, splenic B cells, pre-B cells, triple negative thymocytes, T cell thymoma, and T cell clones), confirming the ubiquitous expression of this message (Yao et al., 1995b). The human, mouse, rat, and viral IL-17 proteins can induce IL-6 secretion by mouse stromal cells, indicating that they all recognize the mouse receptor (Kennedy et al., 1996; Yao et al., 1995a).

1544 Serge Lebecque, FrancËois Fossiez and Elizabeth Bates

SIGNAL TRANSDUCTION

Associated or intrinsic kinases IL-17 induces NFB protein±DNA complexes, consisting of p65/p50 heterodimers in mouse 3T3 fibroblasts and in the rat intestinal epithelial cell line IEC-6 (Yao et al., 1995a; Awane et al., 1999). IL-17 regulates the activities of extracellular signal-regulated kinase ERK1, ERK2, c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein (MAP) kinases in IEC-6 cells and in chondrocytes (ShalomBarak et al., 1998; Awane et al., 1999). Whereas the IL-17-mediated activation of ERK and MAP kinases was mediated through Ras, JNK activation was dependent on functional TRAF6 (but not TRAF2). The correlation between JNK inhibition by dexamethasone and the inhibitory effect of the latter on the response of chondrocytes to IL-17 suggests that JNK is more central to the inflammatory response than the other MAP kinases (Shalom-Barak et al., 1998).

Cytoplasmic signaling cascades These data suggest that IL-17R uses signaling mediators involved in the IL-1R-signaling pathway and that NFB-inducing kinase can serve as the common mediator in the NFB signaling cascades triggered by IL-17, TNF, and IL-1 (Awane et al., 1999). As the analysis of the predicted structure of the cloned IL-17R revealed no homology with the catalytic domain of previously described tyrosine kinasecontaining or -associated cytokine and growth factor receptors (Yao et al., 1995a), the finding that the protein tyrosine kinase inhibitor genistein did not affect IL-17-induced stimulation of G-CSF production by mouse 3T3 fibroblasts was not unexpected (Cai et al., 1998). In contrast, Subramaniam and coworkers have reported that the early signaling events triggered by hIL-17 in human U937 monocytic leukemia cells involve rapid tyrosine phosphorylation of several cellular proteins including Raf-1 serine/ threonine kinase and several members of the JAK and STAT protein families (JAK1, 2, and 3, TYK2, and STAT1, 2, 3, and 4) (Subramaniam et al., 1999a, 1999b). Furthermore, the IL-17-dependent stimulation of IL-1 and TNF production by human macrophages was completely or partially blocked by PKA-specific or nonspecific tyrosine kinase inhibitor, and by PKC or MAP kinase inhibitors, respectively (Jovanovic et al., 1998).

In conclusion, the signaling pathway of IL-17R in stromal cells seems to be shared in part with IL-1R. In contrast, analysis of the biological activities of IL-17 on monocytes/macrophages shows differences between mouse and human and suggests a role for JAK and STAT family members in the latter. It remains unclear, however, how the mouse and human IL-17Rs, which are highly conserved, would signal through two different pathways in two different cell types.

DOWNSTREAM GENE ACTIVATION

Transcription factors activated The NFB activation by IL-17 is in line with the activation of the secretion of several cytokines and chemokines (like IL-1 , IL-6, IL-8, MIP-2, MCP-1) known to be under the transcriptional control of this factor.

BIOLOGICAL CONSEQUENCES OF ACTIVATING OR INHIBITING RECEPTOR AND PATHOPHYSIOLOGY No obvious phenotype was observed after disruption of the IL-17R in mice, although experiments addressing functional alterations have not yet been reported (Spriggs, 1997). Activation of mIL-17R by injecting either rhIL-17 or using adenovirus-mediated gene transfer of the murine IL-17 cDNA targeted to liver resulted in a marked acute neutrophilia, profound stimulation of splenic hematopoiesis, and IL-6dependent protection against lethal challenge with E. coli. There are no data currently available regarding either the consequences of IL-17R dysregulated expression or abnormalities in humans.

THERAPEUTIC UTILITY

Effect of treatment with soluble receptor domain The haematopoietic effect of IL-17, and in particular its ability to indirectly induce acute neutrophilia, suggest a potential therapeutic anti-infectious use in the context of immunosuppression or during bone

IL-17 Receptor 1545 marrow recovery. On the other hand, IL-17R might represent a target for therapeutic inhibition by blocking antibodies, by soluble receptor or by small receptor antagonists in T-dependent autoimmune diseases such as rheumatoid arthritis and multiple sclerosis, in chronic inflammatory conditions of the lung (chronic pulmonary obstructive disease, asthma) or the skin ( psoriasis and atopic dermatitis), in organ graft rejection. Preclinical data also suggest that blocking IL-17R may reduce paracrine IL-6 secretion which acts as a growth factor for some cancers.

References Awane, M., Andres, P. G., Li, D. J., and Reinecker, H. C. (1999). NF-kappa B-inducing kinase is a common mediator of IL-17-, TNF-alpha-, and IL-1 beta-induced chemokine promoter activation in intestinal epithelial cells. J. Immunol. 162, 5337± 5344. Balch, S. G., McKnight, A. J., Seldin, M. F., and Gordon, S. (1998). Cloning of a novel C-type lectin expressed by murine macrophages. J. Biol. Chem. 273, 18656±18664. Cai, X. Y., Gommoll, C. P., Jr., Justice, L., Narula, S. K., and Fine, J. S. (1998). Regulation of granulocyte colony-stimulating factor gene expression by interleukin-17. Immunol. Lett. 62, 51±58. Cosman, D. (1993). The hematopoietin receptor superfamily. Cytokine 5, 95±106. Jovanovic, D. V., Di Battista, J. A., Martel-Pelletier, J., Jolicoeur, F. C., He, Y., Zhang, M., Mineau, F., and Pelletier, J. P. (1998). IL-17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNFalpha, by human macrophages. J. Immunol. 160, 3513±3521. Kennedy, J., Rossi, D. L., Zurawski, S. M., Vega, F., Jr., Kastelein, R. A., Wagner, J. L., Hannum, C. H., and Zlotnik, A. (1996). Mouse IL-17: a cytokine preferentially expressed by alpha beta TCR+ CD4ÿ CD8ÿ T cells. J. Interferon Cytokine Res. 16, 611±617. Shalom-Barak, T., Quach, J., and Lotz, M. (1998). Interleukin-17induced gene expression in articular chondrocytes is associated with activation of mitogen-activated protein kinases and NFkappaB. J. Biol. Chem. 273, 27467±27473. Spriggs, M. K. (1997). Interleukin-17 and its receptor. J. Clin. Immunol. 17, 366±369. Subramaniam, S. V., Cooper, R. S., and Adunyah, S. E. (1999a). Evidence for the involvement of JAK/STAT pathway in the signaling mechanism of interleukin-17. Biochem. Biophys. Res. Commun. 262, 14±19. Subramaniam, S. V., Pearson, L. L., and Adunyah, S. E. (1999b). Interleukin-17 induces rapid tyrosine phosphorylation and activation of raf-1 kinase in human monocytic progenitor cell line U937. Biochem. Biophys. Res. Commun. 259, 172±177. Yao, Z., Fanslow, W. C., Seldin, M. F., Rousseau, A. M., Painter, S. L., Comeau, M. R., Cohen, J. I., and Spriggs, M. K. (1995a). Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity 3, 811±821. Yao, Z., Painter, S. L., Fanslow, W. C., Ulrich, D., Macduff, B. M., Spriggs, M. K., and Armitage, R. J. (1995b). Human IL-17: a novel cytokine derived from T cells. J. Immunol. 155, 5483±5466.

Yao, Z., Spriggs, M. K., Derry, J. M., Strockbine, L., Park, L. S., VandenBos, T., Zappone, J. D., Painter, S. L., and Armitage, R. J. (1997). Molecular characterization of the human interleukin (IL)-17 receptor. Cytokine 9, 794±800.

LICENSED PRODUCTS R&D Systems Human IL-17: Recombinant hIL-17 expressed in E. coli (catalog no.: 317-IL-050) Polyclonal anti-hIL-17 goat antiserum (catalog no.: AF-317-NA) Monoclonal anti-hIL-17 mouse IgG2b antibody (catalog no.: MAB317) Quantitative hIL-17 colorimetric sandwich ELISA (catalog no.: D1700) Mouse IL-17: Recombinant mIL-17 expressed in E. coli (catalog no.: 421-ML-025) Polyclonal anti-mIL-17 goat antiserum (catalog no.: AF-421-NA) Monoclonal anti-mIL-17 mouse IgG2a antibody, selected to neutralize the bioactivity of mIL-17 (catalog no.: MAB421) Monoclonal anti-mIL-17 mouse IgG2a antibody, selected as a capture antibody in mouse IL-17 sandwich ELISAs (catalog no.: MAB721) Quantitative mIL-17 colorimetric sandwich ELISA (catalog no.: D1700) Biosource Quantitative hIL-17 colorimetric solid phase ELISA (catalog no.: KAC1591, KAC1592) Pharmingen Monoclonal anti-mIL-17 mouse IgG1 rat antibody, selected as a capture antibody in mouse IL-17 sandwich ELISAs (catalog no.: 23290D, purified 23291A/D, PE-conjugated 23295A) Monoclonal anti-mIL-17 mouse IgG1 rat antibody, biotinnylated and selected as a detection antibody in mouse IL-17 sandwich ELISAs (catalog no.: 23282D)

ACKNOWLEDGEMENTS The authors wish to thank first P. Golstein and E. Rouvier for sharing the early CTLA-8 data. The members of LIR and of DNAX are aknowledged for their contribution to the identification and the determination of IL-17 functions: J. Abrams, S. AitYahia, J. Banchereau, E. Bates, F. Bazan, J.C. Bories,

1546 Serge Lebecque, FrancËois Fossiez and Elizabeth Bates F. BrieÁre, C. Caux, P. Chomarat, B. Das Mahapatra, O. Djossou, L. Flores-Romo, C. Gaillard, E. Garcia, P. Garrone, D. Gorman, C. H. Hannum, R. Kastelein, J. Kennedy, P. Krishna, C. Maat, K. Moore, R. Murray, C. Perone, J.J. Pin, S. Saeland, A. Zlotnik, G. Zurawsky, and S. Zurawsky. They

also want to thank J. Chiller, D. de Groote, P. Miossec, S. Narula, J.F. Nicolas, M. Spriggs, E. Tartour, and C. Von Kooten for exchange of unpublished informations and discussions. The editorial assistance of S. Bourdarel has been greatly appreciated.