IL-17 Receptor

6 Pages·0.073 MB·English

by  Lebecque S., Fossiez F., Bates E.

IL-17 Receptor
Serge Lebecque*, Franc¸ ois Fossiez and Elizabeth Bates
Laboratory for Immunological Research, Schering-Plough, 27 Chemin des Peupliers, Dardilly,
69572, France
*corresponding author tel: [phone], fax: [phone], e-mail: [email protected]
DOI: 10.1006/rwcy.2000.14010.
SUMMARY GENE
A ubiquitously expressed, large (864aa) mouse mem- Accession numbers
brane glycoprotein has been cloned after its binding
to soluble vIL-17–Fc fusion protein. This receptor, Human IL-17R mRNA: U58917
which also binds CTLA-8, is unrelated to previously Mouse IL-17R mRNA: U31993
identified cytokine receptor families. The cDNA
encodingahumanhomologofthemIL-17Rhasbeen
isolated by crosshybridization. Like its mouse Sequence
counterpart,thehumanIL-17R(866aa)isalsoubiqui-
tously expressed. Monoclonal antibodies against the See Figure 1.
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 Chromosome location and linkages
activities suggest the existence of another, as yet
unidentified, high-affinity IL-17R chain. The chromosomal localization of IL-17R is not
homologousbetweenmouse(chromosome6,between
Raf1andCD4,inthevicinityoftherecentlydescribed
BACKGROUND macrophage-restrictedgroupIIC-typelectinmclgene
locus (Yao et al., 1995b; Balch et al., 1998) and
human (chromosome 22, between markers F8VWFP
Discovery
and D22S420) (Yao et al., 1997).
A mouse cDNA encoding an IL-17-binding protein
hasbeenclonedusingachimericproteincomprisinga PROTEIN
portion of the Fc region of human IgG1 followed by
aminoacids19–151ofvIL-17(Yaoetal.,1995a).The
Accession numbers
vIL-17–Fc fusion protein specifically bound the
murine thymoma cell line EL4, from which a cDNA
Human IL-17R: U58917
library was screened to isolate the gene encoding the
Mouse IL-17R: U31993
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
Sequence
the mouse cDNA as a probe, the human homolog
was cloned from a human T cell library (Yao et al.,
1997). See Figure 2.
1542 Serge Lebecque, Franc¸ois 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 close to the mIL-17R transmembrane domain is
IL-17R. highlyconservedamongcytokinereceptors.Whileno
homology with tyrosine kinase catalytic domains
Human IL-17R could be found in the large cytoplasmic tail, two
MGAARSPPSA VPGPLLGLLL LLLGVLAPGG ASLRLLDHRA LVCSQPGLNC acidicregionsandaserine-richregionarealsopresent
TVKNSTCLDD SWIHPRNLTP SSPKDLQIQL HFAHTQQGDL FPVAHIEWTL
in the IL-2R(cid:12) chain, the IL-4R, and the G-CSFR.
QTDASILYLE GAELSVLQLN TNERLCVRFE FLSKLRHHHR RWRFTFSHFV
VDPDQEYEVT VHHLPKPIPD GDPNHQSKNF LVPDCEHARM KVTTPCMSSG The molecular mass of the molecule immunoprecipi-
SLWDPNITVE TLEAHQLRVS FTLWNESTHY QILLTSFPHM ENHSCFEHMH tated using the m202 anti-hIL-17R antibody is larger
HIPAPRPEEF HQRSNVTLTL RNLKGCCRHQ VQIQPFFSSC LNDCLRHSAT
(128–132kDa) than predicted from the hIL-17R
VSCPEMPDTP EPIPDYMPLW VYWFITGISI LLVGSVILLI VCMTWRLAGP
GSEKYSDDTK YTDGLPAADL IPPPLKPRKV WIIYSADHPL YVDVVLKFAQ cDNA sequence. Expression of hIL-17R in the
FLLTACGTEV ALDLLEEQAI SEAGVMTWVG RQKQEMVESN SKIIVLCSRG presence of tunicamycin demonstrated that the N-
TRAKWQALLG RGAPVRLRCD HGKPVGDLFT AAMNMILPDF KRPACFGTYV
linked glycosylation sites of the extracellular domain
VCYFSEVSCD GDVPDLFGAA PRYPLMDRFE EVYFRIQDLE MFQPGRMHRV
GELSGDNYLR SPGGRQLRAA LDRFRDWQVR CPDWFECENL YSADDQDAPS are indeed utilized.
LDEEVFEEPL LPPGTGIVKR APLVREPGSQ ACLAIDPLVG EEGGAAVAKL
EPHLQPRGQP APQPLHTLVL AAEEGALVAA VEPGPLADGA AVRLALAGEG
EACPLLGSPG AGRNSVLFLP VDPEDSPLGS STPMASPDLL PEDVREHLEG
Affinity for ligand(s)
LMLSLFEQSL SCQAQGGCSR PAMVLTDPHT PYEEEQRQSV QSDQGYISRS
SPQPPEGLTE MEEEEEEEQD PGKPALPLSP EDLESLRSLQ RQLLFRQLQK
NSGWDTMGSE SEGPSA
Direct binding assays revealed a relatively weak
Mouse IL-17R affinity for hIL-17 (K values in the range of 2(cid:2)107
MAIRRCWPRV VPGPALGWLL LLLNVLAPGR ASPRLLDFPA PVCAQEGLSC a
to 2(cid:2)108), which was unexpected from the low
RVKNSTCLDD SWIHPKNLTP SSPKNIYINL SVSSTQHGEL VPVLHVEWTL
QTDASILYLE GAELSVLQLN TNERLCVKFQ FLSMLQHHRK RWRFSFSHFV concentrations of IL-17 needed for most half-maxi-
VDPGQEYEVT VHHLPKPIPD GDPNHKSKII FVPDCEDSKM KMTTSCVSSG mal biological activities (between 2 and 50ng/mL).
SLWDPNITVE TLDTQHLRVD FTLWNESTPY QVLLESFSDS ENHSCFDVVK
This discrepancy suggests that an as yet unidentified
QIFAPRQEEF HQRANVTFTL SKFHWCCHHH VQVQPFFSSC LNDCLRHAVT
VPCPVISNTT VPKPVADYIP LWVYGLITLI AILLVGSVIV LIICMTWRLS high-affinity converting subunit might be present on
GADQEKHGDD SKINGILPVA DLTPPPLRPR KVWIVYSADH PLYVEVVLKF IL-17-responsive cells (Yao et al., 1997).
AQFLITACGT EVALDLLEEQ VISEVGVMTW VSRQKQEMVE SNSKIIILCS
RGTQAKWKAI LGWAEPAVQL RCDHWKPAGD LFTAAMNMIL PDFKRPACFG
TYVVCYFSGI CSERDVPDLF NITSRYPLMD RFEEVYFRIQ DLEMFEPGRM
HHVRELTGDN YLQSPSGRQL KEAVLRFQEW QTQCPDWFER ENLCLADGQD Cell types and tissues expressing
LPSLDEEVFE DPLLPPGGGI VKQQPLVREL PSDGCLVVDV CVSEEESRMA
KLDPQLWPQR ELVAHTLQSM VLPAEQVPAA HVVEPLHLPD GSGAAAQLPM the receptor
TEDSEACPLL GVQRNSILCL PVDSDDLPLC STPMMSPDHL QGDAREQLES
LMLSVLQQSL SGQPLESWPR PEVVLEGCTP SEEEQRQSVQ SDQGYISRSS
PQPPEWLTEE EELELGEPVE SLSPEELRSL RKLQRQLFFW ELEKNPGWNS Human IL-17R mRNA is constitutively and widely
LEPRRPTPEE QNPS
expressed,asitwasdetectedbyPCRintotalPBMCs,
in NK cells, in Raji B cell line, in myelomonocytic
THP1 cell line, in lung epithelial cell lines, and in the
Description of protein
embryonal kidney line 293. Cell surface expression
wasconfirmedbyflowcytometricanalysisusinghIL-
The predicted human receptor is a type I membrane 17–Fc(Yao et al., 1997).Likewise, analysisby north-
glycoprotein with a 293 amino acid extracellular ernblotofthetissuedistributionofmIL-17Rshowed
domain, a 21 amino acid transmembrane region, and thatasinglebandofapproximatively3.7kbispresent
525 amino acid cytoplasmic tail. Human and mouse in all tested tissues, with strong signals observed in
IL-17receptorsappearhighlyconservedastheyshare spleen and kidney. Moderate signals are observed in
82% amino acid similarity and 69% identity, and six lung and liver, and weaker signals in brain, testes,
potential N-linked glycosylation sites. Comparison of heart and skeletal muscles. Likewise, northern blot
bothhumanandmouseIL-17Rsequenceswithpublic and RT-PCR detected the mIL-17R mRNA in every
databases revealed no significant homology with celllinetested(includingfetalliverepithelialcells,rat
known nucleotide and protein sequences. IL-17R intestinal epithelial cells, fibroblasts, muscle cells,
does not include structural features of the immuno- mast cells, splenic B cells, pre-B cells, triple negative
globulin superfamilynorof theTNFreceptor family. thymocytes, T cell thymoma, and T cell clones),
The extracellular domain does not contain the confirming the ubiquitous expression of this message
WSXWS motif found in hematopoietin receptor (Yao et al., 1995b).
family members (Cosman, 1993). However, a rela- The human, mouse, rat, and viral IL-17 proteins
tively large proportion of acidic (16%) and proline can induce IL-6 secretion by mouse stromal cells,
(9%) residues is shared with other growth factor indicating that they all recognize the mouse receptor
receptors, and a segment (TPPPLRPRKVW) located (Kennedy et al., 1996; Yao et al., 1995a).
1544 Serge Lebecque, Franc¸ois Fossiez and Elizabeth Bates
SIGNAL TRANSDUCTION In conclusion, the signaling pathway of IL-17R in
stromalcellsseemstobesharedinpartwithIL-1R.In
contrast, analysis of the biological activities of IL-17
Associated or intrinsic kinases
on monocytes/macrophages shows differences
between mouse and human and suggests a role for
IL-17 induces NF(cid:20)B protein–DNA complexes, con-
JAK and STAT family members in the latter. It
sisting of p65/p50 heterodimers in mouse 3T3 fibro-
remainsunclear,however,howthemouseandhuman
blastsandintheratintestinalepithelialcelllineIEC-6
IL-17Rs, which are highly conserved, would signal
(Yao et al., 1995a; Awane et al., 1999). IL-17 regu-
through two different pathways in two different cell
lates the activities of extracellular signal-regulated
types.
kinase ERK1, ERK2, c-Jun N-terminal kinase
(JNK), and p38 mitogen-activated protein (MAP)
kinases in IEC-6 cells and in chondrocytes (Shalom-
DOWNSTREAM GENE
Barak et al., 1998; Awane et al., 1999). Whereas the
ACTIVATION
IL-17-mediated activation of ERK and MAP kinases
was mediated through Ras, JNK activation was
dependent on functional TRAF6 (but not TRAF2). Transcription factors activated
The correlation between JNK inhibition by dexa-
methasone and the inhibitory effect of the latter on The NF(cid:20)B activation by IL-17 is in line with the
the response of chondrocytes to IL-17 suggests that activation of the secretion of several cytokines and
JNK is more central to the inflammatory response chemokines (like IL-1(cid:12), IL-6, IL-8, MIP-2, MCP-1)
than the other MAP kinases (Shalom-Barak et al., known to be under the transcriptional control of this
1998). factor.
Cytoplasmic signaling cascades BIOLOGICAL CONSEQUENCES
OF ACTIVATING OR INHIBITING
These data suggest that IL-17R uses signaling
RECEPTOR AND
mediators involved in the IL-1R-signaling pathway
and that NF(cid:20)B-inducing kinase can serve as the PATHOPHYSIOLOGY
common mediator in the NF(cid:20)B signaling cascades
triggered by IL-17, TNF(cid:11), and IL-1(cid:12) (Awane et al., No obvious phenotype was observed after disruption
1999). of the IL-17R in mice, although experiments ad-
As the analysis of the predicted structure of the dressing functional alterations have not yet been
cloned IL-17R revealed no homology with the cata- reported (Spriggs, 1997). Activation of mIL-17R by
lytic domain of previously described tyrosine kinase- injectingeitherrhIL-17orusingadenovirus-mediated
containing or -associated cytokine and growth factor gene transfer of the murine IL-17 cDNA targeted to
receptors (Yao et al., 1995a), the finding that the liver resulted in a marked acute neutrophilia, pro-
protein tyrosine kinase inhibitor genistein did not foundstimulationofsplenichematopoiesis,andIL-6-
affect IL-17-induced stimulation of G-CSF produc- dependent protection against lethal challenge with
tion by mouse 3T3 fibroblasts was not unexpected E. coli. There are no data currently available regard-
(Cai et al., 1998). In contrast, Subramaniam and ing either the consequences of IL-17R dysregulated
coworkers have reported that the early signaling expression or abnormalities in humans.
eventstriggeredbyhIL-17inhumanU937monocytic
leukemiacellsinvolverapidtyrosinephosphorylation
of several cellular proteins including Raf-1 serine/ THERAPEUTIC UTILITY
threoninekinaseandseveralmembersoftheJAKand
STAT protein families (JAK1, 2, and 3, TYK2, and Effect of treatment with soluble
STAT1, 2, 3, and 4) (Subramaniam et al., 1999a,
receptor domain
1999b). Furthermore, the IL-17-dependent stimula-
tion of IL-1(cid:11) and TNF(cid:11) production by human
macrophages was completely or partially blocked by The haematopoietic effect of IL-17, and in particular
PKA-specificornonspecifictyrosinekinaseinhibitor, its ability to indirectly induce acute neutrophilia,
and by PKC or MAP kinase inhibitors, respectively suggest a potential therapeutic anti-infectious use in
(Jovanovic et al., 1998). the context of immunosuppression or during bone
IL-17 Receptor 1545
marrow recovery. On the other hand, IL-17R might Yao,Z.,Spriggs,M.K.,Derry,J.M.,Strockbine,L.,Park,L.S.,
represent a target for therapeutic inhibition by VandenBos, T., Zappone, J. D., Painter, S. L., and
Armitage, R. J. (1997). Molecular characterization of the
blocking antibodies, by soluble receptor or by small
humaninterleukin(IL)-17receptor.Cytokine9,794–800.
receptor antagonists in T-dependent autoimmune
diseases such as rheumatoid arthritis and multiple
sclerosis, in chronic inflammatory conditions of the LICENSED PRODUCTS
lung (chronic pulmonary obstructive disease, asthma)
or the skin (psoriasis and atopic dermatitis), in organ
R&D Systems
graft rejection. Preclinical data also suggest that
Human IL-17:
blockingIL-17R mayreduce paracrineIL-6 secretion
which acts as a growth factor for some cancers. Recombinant hIL-17 expressed in E. coli (catalog
no.: 317-IL-050)
Polyclonalanti-hIL-17goatantiserum(catalogno.:
AF-317-NA)
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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).HerpesvirusSaimiriencodesanewcyto- The authors wish to thank first P. Golstein and
kine,IL-17,whichbindstoanovelcytokinereceptor.Immunity E. Rouvier for sharing the early CTLA-8 data. The
3,811–821.
members of LIR and of DNAX are aknowledged
Yao, Z., Painter, S. L., Fanslow, W. C., Ulrich, D.,
for their contribution to the identification and the
Macduff, B. M., Spriggs, M. K., and Armitage, R. J. (1995b).
HumanIL-17:anovelcytokinederivedfromTcells.J.Immunol. determination of IL-17 functions: J. Abrams, S. Ait-
155,5483–5466. Yahia,J.Banchereau,E.Bates,F.Bazan,J.C.Bories,
1546 Serge Lebecque, Franc¸ois Fossiez and Elizabeth Bates
F. Brie`re, C. Caux, P.Chomarat, B. Das Mahapatra, also want to thank J. Chiller, D. de Groote,
O. Djossou, L. Flores-Romo, C. Gaillard, E. Garcia, P. Miossec, S. Narula, J.F. Nicolas, M. Spriggs,
P. Garrone, D. Gorman, C. H. Hannum, E. Tartour, and C. Von Kooten for exchange of
R. Kastelein, J. Kennedy, P. Krishna, C. Maat, K. unpublishedinformationsanddiscussions.Theedito-
Moore, R. Murray, C. Perone, J.J. Pin, S. Saeland, rial assistance of S. Bourdarel has been greatly
A. Zlotnik, G. Zurawsky, and S. Zurawsky. They appreciated.