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IL-10 Receptor Rene de Waal Malefyt* Department of Molecular Biology, DNAX Research Institute, 901 California Avenue, Palo Alto, CA 94304-1104, USA *corresponding author tel: 650-496-1164, fax: 650-496-1200, e-mail: [email protected] DOI: 10.1006/rwcy.2000.14005. SUMMARY complementation studies in combination with the IL-10R(cid:11) chain (Kotenko et al., 1997). IL-10 interacts with its tetrameric receptor complex consisting of two IL-10R(cid:11) and two IL-10R(cid:12) chains Structure resulting in the phosphorylation and activation of JAK1 and TYK2 kinases, which in turn phosphor- Both IL-10R(cid:11) and IL-10R(cid:12) belong to the class II ylate two tyrosine residues in the intracytoplasmic cytokine receptor family, together with the receptors parts of the IL-10R(cid:11) chains that form docking sites for IFN(cid:11) and IFN(cid:13). Crystallization of human IL-10 for STAT3. Binding of STAT3 results in phosphor- orviralIL-10tosolubleextracellularIL-10R(cid:11)chains ylation by JAK1 and TYK2 kinases, homo- or hasindicatedthatthestoichiometryoftheIL-10/sIL- heterodimerization and translocation to the nucleus 10R(cid:11) complex contains two IL-10 dimers binding to where it binds to the promoters of IL-10-responsive four shIL-10R(cid:11) monomers (Hoover et al., 1999), genes such as the Fc(cid:13)RI and activates transcription. confirming results from previous gel filtration experi- All IL-10-mediated responses are dependent on acti- ments(Tanetal.,1995).AmodelofIL-10complexed vation of STAT3, but the anti-inflammatory actions with its soluble receptor at high resolution, based on of IL-10 require additional sequences in the distal topologicalsimilaritybetweenIL-10andIFN(cid:13) isalso intracytoplasmic part of the IL-10R(cid:11) chain. available (Zdanov et al., 1996). Main activities and BACKGROUND pathophysiological roles Discovery The main activity for the IL-10 receptor is to bind IL-10 and initiate the transduction of a signaling IL-10 mediates its biological effects by interacting cascade,whichleadstothemodificationofbiological withspecificcellsurfacereceptors.TheIL-10receptor responses. There have been no specific pathophysio- complex consists of at least two separate receptor logicalrolesdescribedfortheIL-10receptorcomplex chains, a ligand-binding IL-10R(cid:11) chain and a IL- itself. The association of IL-10 with disease is 10R(cid:12)chain,whichisessentialforsignaltransduction. described in the IL-10 chapter. Radiolabeled IL-10 and FLAG epitope-tagged IL-10 were initially used to detect specific receptors on IL-10-responsive cells and to enrich for cells expres- GENE sing high numbers of receptors (Tan et al., 1993). Expression cloning strategies led to the isolation of Accession numbers cDNAs encoding murine and human IL-10R(cid:11)- binding proteins (Ho et al., 1993; Liu et al., 1994). Subsequently, an orphan class II cytokine receptor Mouse IL-10R(cid:11): L12120 was identified as the IL-10R(cid:12) chain by functional Human IL-10R(cid:11): U00672, NM001558 1496 Rene de Waal Malefyt Mouse IL-10R(cid:12): U53696 level. The first extracellular immunoglobulin-like Human IL-10R(cid:12): NM000628 binding domain of the hIL-10R(cid:11) lacks the intracel- lular disulfide bridge and the intracytoplasmic tail lacks one tyrosine residue as compared to the mIL-10R(cid:11), although neither of these differences Sequence seem functionally significant. See Figure 1. Affinity for ligand(s) Mouse and human IL-10 receptor complexes bind Chromosome location and linkages their ligand with high affinity (K (cid:24)35–200pM). d Human IL-10 interacts with mIL-10R complex, but Mouse IL-10R(cid:11): 9 mouse IL-10 does not bind to the hIL-10R complex, Human IL-10R(cid:11): 11q23.3 which is consistent with the observed species specifi- Mouse IL-10R(cid:12): 16 cities of these cytokines. The affinity and specific Human IL-10R(cid:12): 21q22.1–21q22.2 activity of human IL-10 is (cid:24)10-fold lower on cells The structure of the IL-10R(cid:12) loci is conserved expressing mixed receptor complexes consisting of among human, mouse, and chicken but not in fish hIL-10R(cid:11) and mIL-10R(cid:12) chains as compared to (Reboul et al., 1999). mIL-10R(cid:11)(cid:12) complexes. EBV-derived viral IL-10 (vIL-10) boundhuman and mouse IL-10R(cid:11) transfec- tantswithatleasta1000-foldloweraffinitythantheir corresponding cellular ligand/receptor combinations. PROTEIN However, vIL-10 could activate cells through mIL- 10R or hIL-10R with a specific activity identical to Accession numbers thecellularcytokinedependingonthecelltypeandin agreement with the limited biological spectrum of Mouse IL-10R(cid:11): AAA16156.1 vIL-10 as compared to cellular IL-10. Recently, it Human IL-10R(cid:11): NP001549.1 has been shown that a single amino acid substitution Mouse IL-10R(cid:12): AAC53062 at position 87 (I-A) is responsible for the reduced Human IL-10R(cid:12): NP000619 immunostimulatoryactivityofviralIL-10(Dingetal., 2000). All responses to vIL-10 are dependent on the expression of the IL-10R(cid:11) as indicated by a blocking anti-hIL-10R(cid:11) monoclonal antibody (Liu et al., Description of protein 1997). CmvIL-10, a viral homolog of IL-10 identified in human cytomegalovirus ORF UL111a, also binds The mIL-10R(cid:11) and hIL-10R(cid:11) polypeptides are to the hIL-10R complex and induces signal transduc- composedof576and578aminoacidresiduesrespec- tion events and biological activities (Kotenko et al., tively, whereas mIL-10R(cid:12) and hIL-10R(cid:12) chains 2000).Interestingly,unlikeEBV-derivedvIL-10,which consist of 349 and 325 amino acid residues respec- is 84% homologous to hIL-10, cmvIL-10 displays tively. IL-10R(cid:11) chains are expressed as 90–120kDa only 27% homology to hIL-10. proteinsandIL-10R(cid:12) chainshaveamolecularweight of (cid:24)40kDa. IL-10R(cid:11) chains contain four (mouse) to six (human) N-linked glycosylation sites which Cell types and tissues expressing are used. Positive cells express only a few hundred the receptor receptor complexes per cell. IL-10R(cid:11) chains are expressed on cells of hemato- Relevant homologies and species poietic origin including T cells, B cells, monocytes, macrophages,dendriticcells,NKcells,mastcells,and differences varioushematopoieticprogenitors.Inaddition,tumor cells of hematopoietic origin, such as myeloma cells, Mouse and human IL-10R(cid:11) chains are (cid:24)60% BCLL,microglia,etc.havebeendescribedtoexpress identical and 73% similar. Mouse and human IL- the IL-10R(cid:11) The IL-10R(cid:11) is present on epithelial 10R(cid:12) chains are 69% identical at the amino acid cellsfrommurinesmallandlargeintestine,onhuman IL-10 Receptor 1497 Figure 1 Nucleotide sequences for the mouse and human IL-10R(cid:11) genes and the mouse and human IL-10R(cid:12) genes. Mouse IL-10Ra: 1 CCATTGTGCT GGAAAGCAGG ACGCGCCGGC CGGAGGCGTA AAGGCCGGCT CCAGTGGACG 61 ATGCCGCTGT GCGCCCAGGA TGTTGTCGCG TTTGCTCCCA TTCCTCGTCA CGATCTCCAG 121 CCTGAGCCTA GAATTCATTG CATACGGGAC AGAACTGCCA AGCCCTTCCT ATGTGTGGTT 181 TGAAGCCAGA TTTTTCCAGC ACATCCTCCA CTGGAAACCT ATCCCAAACC AGTCTGAGAG 241 CACCTACTAT GAAGTGGCCC TCAAACAGTA CGGAAACTCA ACCTGGAATG ACATCCATAT 301 CTGTAGAAAG GCTCAGGCAT TGTCCTGTGA TCTCACAACG TTCACCCTGG ATCTGTATCA 361 CCGAAGCTAT GGCTACCGGG CCAGAGTCCG GGCAGTGGAC AACAGTCAGT ACTCCAACTG 421 GACCACCACT GAGACTCGCT TCACAGTGGA TGAAGTGATT CTGACAGTGG ATAGCGTGAC 481 TCTGAAAGCA ATGGACGGCA TCATCTATGG GACAATCCAT CCCCCCAGGC CCACGATAAC 541 CCCTGCAGGG GATGAGTACG AACAAGTCTT CAAGGATCTC CGAGTTTACA AGATTTCCAT 601 CCGGAAGTTC TCAGAACTAA AGAATGCAAC CAAGAGAGTG AAACAGGAAA CCTTCACCCT 661 CACGGTCCCC ATAGGGGTGA GAAAGTTTTG TGTCAAGGTG CTGCCCCGCT TGGAATCCCG 721 AATTAACAAG GCAGAGTGGT CGGAGGAGCA GTGTTTACTT ATCACGACGG AGCAGTATTT 781 CACTGTGACC AACCTGAGCA TCTTAGTCAT ATCTATGCTG CTATTCTGTG GAATCCTGGT 841 CTGTCTGGTT CTCCAGTGGT ACATCCGGCA CCCGGGGAAG TTGCCTACAG TCCTGGTCTT 901 CAAGAAGCCT CACGACTTCT TCCCAGCCAA CCCTCTCTGC CCAGAAACTC CCGATGCCAT 961 TCACATCGTG GACCTGGAGG TTTTCCCAAA GGTGTCACTA GAGCTGAGAG ACTCAGTCCT 1021 GCATGGCAGC ACCGACAGTG GCTTTGGCAG TGGTAAACCA TCACTTCAGA CTGAAGAGTC 1081 CCAATTCCTC CTCCCTGGCT CCCACCCCCA GATACAGGGG ACTCTGGGAA AAGAAGAGTC 1141 TCCAGGGCTA CAGGCCACCT GTGGGGACAA CACGGACAGT GGGATCTGCC TGCAGGAGCC 1201 CGGCTTACAC TCCAGCATGG GGCCCGCCTG GAAGCAGCAG CTTGGATATA CCCATCAGGA 1261 CCAGGATGAC AGTGACGTTA ACCTAGTCCA GAACTCTCCA GGGCAGCCTA AGTACACACA 1321 GGATGCATCT GCCTTGGGCC ATGTCTGTCT CCTAGAACCT AAAGCCCCTG AGGAGAAAGA 1381 CCAAGTCATG GTGACATTCC AGGGCTACCA GAAACAGACC AGATGGAAGG CAGAGGCAGC 1441 AGGCCCAGCA GAATGCTTGG ACGAAGAGAT TCCCTTGACA GATGCCTTTG ATCCTGAACT 1501 TGGGGTACAC CTGCAGGATG ATTTGGCTTG GCCTCCACCA GCTCTGGCCG CAGGTTATTT 1561 GAAACAGGAG TCTCAAGGGA TGGCTTCTGC TCCACCAGGG ACACCAAGTA GACAGTGGAA 1621 TCAACTGACC GAAGAGTGGT CACTCCTGGG TGTGGTTAGC TGTGAAGATC TAAGCATAGA 1681 AAGTTGGAGG TTTGCCCATA AACTTGACCC TCTGGACTGT GGGGCAGCCC CTGGTGGCCT 1741 CCTGGATAGC CTTGGCTCTA ACCTGGTCAC CCTGCCGTTG ATCTCCAGCC TGCAGGTAGA 1801 AGAATGACAG CGGCTAAGAG TTATTTGTAT TCCAGCCATG CCTGCTCCCC TCCCTGTACC 1861 TGGGAGGCTC AGGAGTCAAA GAAATATGTG GGTCCTTTTC TGCAGACCTA CTGTGACCAG 1921 CTAGCCAGGC TCCACGGGGC AAGGAAAGGC CATCTTGATA CACGAGTGTC AGGTACATGA 1981 GAGGTTGTGG CTAGTCTGCT GAGTGAGGGT CTGTAGATAC CAGCAGAGCT GAGCAGGATT 2041 GACAGAGACC TCCTCATGCC TCAGGGCTGG CTCCTACACT GGAAGGACCT GTGTTTGGGT 2101 GTAACCTCAG GGCTTTCTGG ATGTGGTAAG ACTGTAGGTC TGAAGTCAGC TGAGCCTGGA 2161 TGTCTGCGGA GGTGTTGGAG TGGCTAGCCT GCTACAGGAT AAAGGGAAGG CTCAAGAGAT 2221 AGAAGGGCAG AGCATGAGCC AGGTTTAATT TTGTCCTGTA GAGATGGTCC CCAGCCAGGA 2281 TGGGTTACTT GTGGCTGGGA GATCTTGGGG TATACACCAC CCTGAATGAT CAGCCAGTCA 2341 ATTCAGAGCT GTGTGGCAAA AGGGACTGAG ACCCAGAATT TCTGTTCCTC TTGTGAGGTG 2401 TCTCTGCTAC CCATCTGCAG ACAGACATCT TCATCTTTTT ACTATGGCTG TGTCCCCTGA 2461 ATTACCAGCA GTGGCCAAGC CATTACTCCC TGCTGCTCAC TGTTGTGACG TCAGACCAGA 2521 CCAGACGCTG TCTGTCTGTG TTAGTACACT ACCCTTTAGG TGGCCTTTGG GCTTGAGCAC 2581 TGGCCCAGGC TTAGGACTTA TGTCTGCTTT TGCTGCTAAT CTCTAACTGC AGACCCAGAG 2641 AACAGGGTGC TGGGCTGACA CCTCCGTGTT CAGCTGTGTG ACCTCCGACC AGCAGCTTCC 2701 TCAGGGGACT AAAATAATGA CTAGGTCATT CAGAAGTCCC TCATGCTGAA TGTTAACCAA 2761 GGTGCCCCTG GGGTGATAGT TTAGGTCCTG CAACCTCTGG GTTGGAAGGA AGTGGACTAC 2821 GGAAGCCATC TGTCCCCCTG GGGAGCTTCC ACCTCATGCC AGTGTTTCAG AGATCTTGTG 2881 GGAGCCTAGG GCCTTGTGCC AAGGGAGCTG CTAGTCCCTG GGGTCTAGGG CTGGTCCCTG 2941 CCTCCCTATA CTGCGTTTGA GACCTGTCTT CAAATGGAGG CAGTTTGCAG CCCCTAAGCA 3001 AGGATGCTGA GAGAAGCAGC AAGGCTGCTG ATCCCTGAGC CCAGAGTTTC TCTGAAGCTT 3061 TCCAAATACA GACTGTGTGA CGGGGTGAGG CCAGCCATGA ACTTTGGCAT CCTGCCGAGA 3121 AGGTCATGAC CCTAATCTGG TACGAGAGCT CCTTCTGGAA CTGGGCAAGC TCTTTGAGAC 3181 CCCCCTGGAA CCTTTATTTA TTTATTTGCT CACTTATTTA TTGAGGAAGC AGCGTGGCAC 3241 AGGCGCAAGG CTCTGGGTCT CTCAGGAGGT CTAGATTTGC CTGCCCTGTT TCTAGCTGTG 3301 TGACCTTGGG CAAGTCACGT TTCCTCGTGG AGCCTCAGTT TTCCTGTCTG TATGCAAAGC 3361 TTGGAAATTG AAATGTACCT GACGTGCTCC ATCCCTAGGA GTGCTGAGTC CCACTGAGAA 3421 AGCGGGCACA GACGCCTCAA ATGGAACCAC AAGTGGTGTG TGTTTTCATC CTAATAAAAA 3481 GTCAGGTGTT TTGTGGA 1498 Rene de Waal Malefyt Figure 1 (Continued) Human IL-10Ra: 1 AAAGAGCTGG AGGCGCGCAG GCCGGCTCCG CTCCGGCCCC GGACGATGCG GCGCGCCCAG 61 GATGCTGCCG TGCCTCGTAG TGCTGCTGGC GGCGCTCCTC AGCCTCCGTC TTGGCTCAGA 121 CGCTCATGGG ACAGAGCTGC CCAGCCCTCC GTCTGTGTGG TTTGAAGCAG AATTTTTCCA 181 CCACATCCTC CACTGGACAC CCATCCCAAA TCAGTCTGAA AGTACCTGCT ATGAAGTGGC 241 GCTCCTGAGG TATGGAATAG AGTCCTGGAA CTCCATCTCC AACTGTAGCC AGACCCTGTC 301 CTATGACCTT ACCGCAGTGA CCTTGGACCT GTACCACAGC AATGGCTACC GGGCCAGAGT 361 GCGGGCTGTG GACGGCAGCC GGCACTCCAA CTGGACCGTC ACCAACACCC GCTTCTCTGT 421 GGATGAAGTG ACTCTGACAG TTGGCAGTGT GAACCTAGAG ATCCACAATG GCTTCATCCT 481 CGGGAAGATT CAGCTACCCA GGCCCAAGAT GGCCCCCGCG AATGACACAT ATGAAAGCAT 541 CTTCAGTCAC TTCCGAGAGT ATGAGATTGC CATTCGCAAG GTGCCGGGAA ACTTCACGTT 601 CACACACAAG AAAGTAAAAC ATGAAAACTT CAGCCTCCTA ACCTCTGGAG AAGTGGGAGA 661 GTTCTGTGTC CAGGTGAAAC CATCTGTCGC TTCCCGAAGT AACAAGGGGA TGTGGTCTAA 721 AGAGGAGTGC ATCTCCCTCA CCAGGCAGTA TTTCACCGTG ACCAACGTCA TCATCTTCTT 781 TGCCTTTGTC CTGCTGCTCT CCGGAGCCCT CGCCTACTGC CTGGCCCTCC AGCTGTATGT 841 GCGGCGCCGA AAGAAGCTAC CCAGTGTCCT GCTCTTCAAG AAGCCCAGCC CCTTCATCTT 901 CATCAGCCAG CGTCCCTCCC CAGAGACCCA AGACACCATC CACCCGCTTG ATGAGGAGGC 961 CTTTTTGAAG GTGTCCCCAG AGCTGAAGAA CTTGGACCTG CACGGCAGCA CAGACAGTGG 1021 CTTTGGCAGC ACCAAGCCAT CCCTGCAGAC TGAAGAGCCC CAGTTCCTCC TCCCTGACCC 1081 TCACCCCCAG GCTGACAGAA CGCTGGGAAA CGGGGAGCCC CCTGTGCTGG GGGACAGCTG 1141 CAGTAGTGGC AGCAGCAATA GCACAGACAG CGGGATCTGC CTGCAGGAGC CCAGCCTGAG 1201 CCCCAGCACA GGGCCCACCT GGGAGCAACA GGTGGGGAGC AACAGCAGGG GCCAGGATGA 1261 CAGTGGCATT GACTTAGTTC AAAACTCTGA GGGCCGGGCT GGGGACACAC AGGGTGGCTC 1321 GGCCTTGGGC CACCACAGTC CCCCGGAGCC TGAGGTGCCT GGGGAAGAAG ACCCAGCTGC 1381 TGTGGCATTC CAGGGTTACC TGAGGCAGAC CAGATGTGCT GAAGAGAAGG CAACCAAGAC 1441 AGGCTGCCTG GAGGAAGAAT CGCCCTTGAC AGATGGCCTT GGCCCCAAAT TCGGGAGATG 1501 CCTGGTTGAT GAGGCAGGCT TGCATCCACC AGCCCTGGCC AAGGGCTATT TGAAACAGGA 1561 TCCTCTAGAA ATGACTCTGG CTTCCTCAGG GGCCCCAACG GGACAGTGGA ACCAGCCCAC 1621 TGAGGAATGG TCACTCCTGG CCTTGAGCAG CTGCAGTGAC CTGGGAATAT CTGACTGGAG 1681 CTTTGCCCAT GACCTTGCCC CTCTAGGCTG TGTGGCAGCC CCAGGTGGTC TCCTGGGCAG 1741 CTTTAACTCA GACCTGGTCA CCCTGCCCCT CATCTCTAGC CTGCAGTCAA GTGAGTGACT 1801 CGGGCTGAGA GGCTGCTTTT GATTTTAGCC ATGCCTGCTC CTCTGCCTGG ACCAGGAGGA 1861 GGGCCCTGGG GCAGAAGTTA GGCACGAGGC AGTCTGGGCA CTTTTCTGCA AGTCCACTGG 1921 GGCTGGCCCA GCCAGGCTGC AGGGCTGGTC AGGGTGTCTG GGGCAGGAGG AGGCCAACTC 1981 ACTGAACTAG TGCAGGGTAT GTGGGTGGCA CTGACCTGTT CTGTTGACTG GGGCCCTGCA 2041 GACTCTGGCA GAGCTGAGAA GGGCAGGGAC CTTCTCCCTC CTAGGAACTC TTTCCTGTAT 2101 CATAAAGGAT TATTTGCTCA GGGGAACCAT GGGGCTTTCT GGAGTTGTGG TGAGGCCACC 2161 AGGCTGAAGT CAGCTCAGAC CCAGACCTCC CTGCTTAGGC CACTCGAGCA TCAGAGCTTC 2221 CAGCAGGAGG AAGGGCTGTA GGAATGGAAG CTTCAGGGCC TTGCTGCTGG GGTCATTTTT 2281 AGGGGAAAAA GGAGGATATG ATGGTCACAT GGGGAACCTC CCCTCATCGG GCCTCTGGGG 2341 CAGGAAGCTT GTCACTGGAA GATCTTAAGG TATATATTTT CTGGACACTC AAACACATCA 2401 TAATGGATTC ACTGAGGGGA GACAAAGGGA GCCGAGACCC TGGATGGGGC TTCCAGCTCA 2461 GAACCCATCC CTCTGGTGGG TACCTCTGGC ACCCATCTGC AAATATCTCC CTCTCTCCAA 2521 CAAATGGAGT AGCATCCCCC TGGGGCACTT GCTGAGGCCA AGCCACTCAC ATCCTCACTT 2581 TGCTGCCCCA CCATCTTGCT GACAACTTCC AGAGAAGCCA TGGTTTTTTG TATTGGTCAT 2641 AACTCAGCCC TTTGGGCGGC CTCTGGGCTT GGGCACCAGC TCATGCCAGC CCCAGAGGGT 2701 CAGGGTTGGA GGCCTGTGCT TGTGTTTGCT GCTAATGTCC AGCTACAGAC CCAGAGGATA 2761 AGCCACTGGG CACTGGGCTG GGGTCCCTGC CTTGTTGGTG TTCAGCTGTG TGATTTTGGA 2821 CTAGCCACTT GTCAGAGGGC CTCAATCTCC CATCTGTGAA ATAAGGACTC CACCTTTAGG 2881 GGACCCTCCA TGTTTGCTGG GTATTAGCCA AGCTGGTCCT GGGAGAATGC AGATACTGTC 2941 CGTGGACTAC CAAGCTGGCT TGTTTCTTAT GCCAGAGGCT AACAGATCCA ATGGGAGTCC 3001 ATGGTGTCAT GCCAAGACAG TATCAGACAC AGCCCCAGAA GGGGGCATTA TGGGCCCTGC 3061 CTCCCCATAG GCCATTTGGA CTCTGCCTTC AAACAAAGGC AGTTCAGTCC ACAGGCATGG 3121 AAGCTGTGAG GGGACAGGCC TGTGCGTGCC ATCCAGAGTC ATCTCAGCCC TGCCTTTCTC 3181 TGGAGCATTC TGAAAACAGA TATTCTGGCC CAGGGAATCC AGCCATGACC CCCACCCCTC 3241 TGCCAAAGTA CTCTTAGGTG CCAGTCTGGT AACTGAACTC CCTCTGGAGG CAGGCTTGAG 3301 GGAGGATTCC TCAGGGTTCC CTTGAAAGCT TTATTTATTT ATTTTGTTCA TTTATTTATT 3361 GGAGAGGCAG CATTGCACAG TGAAAGAATT CTGGATATCT CAGGAGCCCC GAAATTCTAG 3421 CTCTGACTTT GCTGTTTCCA GTGGTATGAC CTTGGAGAAG TCACTTATCC TCTTGGAGCC 3481 TCAGTTTCCT CATCTGCAGA ATAATGACTG ACTTGTCTAA TTCATAGGGA TGTGAGGTTC 3541 TGCTGAGGAA ATGGGTATGA ATGTGCCTTG AACACAAAGC TCTGTCAATA AGTGATACAT 3601 GTTTTTTATT CCAATAAATT GTCAAGACCA CA IL-10 Receptor 1499 Figure 1 (Continued) Mouse IL-10Rb: 1 ACATGGCCCC GTGCGTGGCG GGCTGGCTGG GTGGCTTCCT TCTGGTGCCA GCTCTAGGAA 61 TGATTCCACC CCCTGAGAAG GTCAGAATGA ATTCAGTTAA TTTCAAGAAC ATTCTACAGT 121 GGGAGGTACC TGCTTTCCCC AAAACGAACC TGACTTTCAC AGCTCAGTAT GAAAGTTACA 181 GGTCTTTCCA AGATCACTGC AAGCGCACTG CCTCGACTCA GTGCGACTTC TCTCATCTTT 241 CTAAATACGG AGACTACACT GTGAGAGTCA GGGCTGAATT GGCGGATGAA CATTCGGAGT 301 GGGTCAATGT CACCTTCTGC CCCGTGGAAG ACACCATCAT TGGACCTCCT GAGATGCAGA 361 TAGAATCCCT TGCTGAGTCT TTACACCTGC GTTTCTCAGC CCCACAAATT GAGAATGAGC 421 CTGAGACGTG GACCTTGAAG AACATTTATG ACTCATGGGC TTACAGAGTG CAATACTGGA 481 AAAATGGGAC TAATGAGAAG TTTCAAGTTG TGTCTCCGTA CGACTCTGAG GTCCTCCGGA 541 ACCTGGAGCC GTGGACAACT TACTGCATTC AAGTTCAAGG GTTTCTTCTC GACCAGAACA 601 GAACAGGAGA GTGGAGTGAA CCCATCTGTG AACGGACAGG CAATGACGAA ATAACCCCTT 661 CCTGGATTGT GGCCATCATC CTCATAGTCT CCGTCCTGGT GGTCTTCCTC TTCCTCCTGG 721 GCTGCTTTGT CGTGCTGTGG CTCATTTATA AGAAGACCAA GCATACCTTC CGTTCTGGGA 781 CGTCTCTTCC ACAGCACCTG AAGGAGTTTC TGGGCCACCC CCATCACAGC ACGTTTCTGC 841 TGTTCTCCTT CCCTCCCCCC GAGGAGGCCG AGGTGTTCGA CAAACTAAGC ATCATCAGCG 901 AAGAGTCTGA AGGCAGCAAG CAGAGTCCTG AAGACAACTG TGCCTCAGAG CCCCCGTCTG 961 ATCCAGGGCC TCGGGAGCTG GAGTCCAAGG ATGAAGCTCC CTCACCTCCA CACGATGACC 1021 CCAAACTGCT CACGTCGACC TCAGAAGTAT GACCAGAGAG CCACCTGAAA AAACTCCAAA 1081 TCTAGAACTT CCTGATGCTG CACTGGTACA CACAACCAAA GAGCTAGGTT TTAAACACTC 1141 TACTTGGGAA TTTGCTGCCA TATAAAGACT AATAATTTAG GGACTGAGGG TGTAGCTCAG 1201 TGACTAGAGC TCTTACTTGG CACACATGAA GTCCTAGCTT CGATCCCCAA CACCATATAA 1261 ACCAGGGATG GGGGCACCTA CCTATAAGCC CAGCACTTTG GAGGTAGAGG CAGGAGGATC 1321 ACAGTCATCT TGAACTATAC AGGGAGTTCA AGGCCAAGCT GGACTAGAGA CCCTGTCTAA 1381 GAGAGAGAGA GAGAACTTAT ATATTTTATG GCCACTGAAT GTAATTTGAG CCCTTTGTGC 1441 TCACTAAAAC AAGGATCACA TTTAACTTGT GACAAACAAA AATATTTTAA ATGGGGGGGG 1501 GGGCATGGAA ACACTATGAA ATTATAAGAA TGCCTATAGA CCACCCGCAT CTCAAAAGTG 1561 GTTGGCCCCA TGCGGGACAG ACATGAACAT TTTGGATTCC CAAGGAGCAA AGAGATTTCC 1621 TTCCTTACCT GTGTGTTTTG TATTAATATT AGTGTTCTGT AAATATTCTA Human IL-10Rb: 1 ATGGCGTGGA GTCTTGGGAG CTGGCTGGGT GGCTGCCTGC TGGTGTCAGC ATTGGGAATG 61 GTACCACCTC CCGAAAATGT CAGAATGAAT TCTGTTAATT TCAAGAACAT TCTACAGTGG 121 GAGTCACCTG CTTTTGCCAA AGGGAACCTG ACTTTCACAG CTCAGTACCT AAGTTATAGG 181 ATATTCCAAG ATAAATGCAT GAATACTACC TTGACGGAAT GTGATTTCTC AAGTCTTTCC 241 AAGTATGGTG ACCACACCTT GAGAGTCAGG GCTGAATTTG CAGATGAGCA TTCAGACTGG 301 GTAAACATCA CCTTCTGTCC TGTGGATGAC ACCATTATTG GACCCCCTGG AATGCAAGTA 361 GAAGTACTTG ATGATTCTTT ACATATGCGT TTCTTAGCCC CTAAAATTGA GAATGAATAC 421 GAAACTTGGA CTATGAAGAA TGTGTATAAC TCATGGACTT ATAATGTGCA ATACTGGAAA 481 AACGGTACTG ATGAAAAGTT TCAAATTACT CCCCAGTATG ACTTTGAGGT CCTCAGAAAC 541 CTGGAGCCAT GGACAACTTA TTGTGTTCAA GTTCGAGGGT TTCTTCCTGA TCGGAACAAA 601 GCTGGGGAAT GGAGTGAGCC TGTCTGTGAG CAAACAACCC ATGACGAAAC GGTCCCCTCC 661 TGGATGGTGG CCGTCATCCT CATGGCCTCG GTCTTCATGG TCTGCCTGGC ACTCCTCGGC 721 TGCTTCTCCT TGCTGTGGTG CGTTTACAAG AAGACAAAGT ACGCCTTCTC CCCTAGGAAT 781 TCTCTTCCAC AGCACCTGAA AGAGGTAGGT AGGATGGAGT GA epidermal cells and keratinocytes and can be induced expression of IL-10R(cid:11) mRNA by human T cell on fibroblasts (Michel et al., 1997; Denning et al., clones was downregulated following activation (Liu 2000). et al., 1994). IL-10R(cid:12) chain seems to be expressed ubiquitously. Release of soluble receptors Regulation of receptor expression No data has been published on the production and IL-10R(cid:11) expression is induced in fibroblasts by LPS releaseofsolubleIL-10receptorsinnormalordisease activation(Weber-Nordtetal.,1994).Incontrast,the states. 1500 Rene de Waal Malefyt SIGNAL TRANSDUCTION STAT1 (Ito et al., 1999). This may be mediated by the rapid STAT3-dependent induction of SOCS3 Associated or intrinsic kinases (suppressor of cytokine signaling 3). SOCS proteins are members of a family of molecules that interfere withJAK/STATsignaltransductionpathways.Alter- NeithertheIL-10R(cid:11)northeIL-10R(cid:12)chainpossesses natively, differences in DNA-binding activity and anintrinsickinaseactivity.However,IL-10treatment composition of IL-10-induced STAT1 and IFN- of cells induces phosphorylation of the IL-10R(cid:11)- induced STAT1 complexes may play a role in the associated JAK1 and the IL-10R(cid:12)-associated TYK2 differential responses to IL-10 and IFN(cid:13) (Yamaoka kinases (Finbloom and Winestock, 1995; Ho et al., et al., 1999). 1995). Interestingly, in contrast to IFN(cid:13), IL-10 failed to upregulate Fc(cid:13)RI expression and GRR (IFN(cid:13) response region)- or SIE (serum-inducible element)- Cytoplasmic signaling cascades binding activity in human neutrophils, despite the presenceofafunctionalIL-10Rcomplex,andSTAT1 PhosphorylationofJAK1(Januskinase1)andTYK2 andSTAT3expressionbythesecells(Bovolentaetal., kinases by IL-10 binding to the receptor complex 1998). IL-10 did induce SOCS3 expression in neutro- activates their kinase activity and leads to phosphor- phils, indicating that activation of STAT1 or STAT3 ylation of two tyrosine residues, which are part of phosphorylationis notrequired forSOCS3induction thecytokinereceptorbox3motif,(Y446andY496in in these cells as it is in monocytes (Cassatella et al., hIL-10R(cid:11) and Y427 and Y477 in mIL-10R(cid:11)) in 1999). the intracytoplasmic tail of the IL-10R(cid:11) chain. Othersignalingpathwaysthathavebeenimplicated Phosphorylation of at least one tyrosine residue is in biological responses to IL-10 include NF(cid:20)B, phos- sufficient for a biological response. These phosphor- phatidylinositol 3-kinase, p70 S6 kinase, and MAP ylatedtyrosineresiduesthenserveasdockingsitesfor kinase cascades, but none of these have been directly the latent transcription factor STAT3 (signal trans- linked to molecules that interact with the IL-10 ducer and activator of transcription 3) which in turn receptor (De Waal Malefyt and Moore, 1998). becomes phosphorylated by the activated JAK1 and TYK2kinases.PhosphorylatedSTATmoleculessub- DOWNSTREAM GENE sequently form homo- or heterodimers and translo- cate from the cytoplasm to the nucleus, where they ACTIVATION bind with high affinity to STAT-binding elements (SBE) in the promoters of IL-10-responsive genes Transcription factors activated (Laietal.,1996;Wehingeretal.,1996).IL-10canalso activate STAT5 and/or only STAT1 DNA-binding IL-10 activates STAT1, STAT3, and in some cell activityinsomecelltypes(Weber-Nordtetal.,1996a; types STAT5 DNA-binding activity and transcrip- Zocchia et al., 1997). Whereas STAT3 is directly tional activation (Finbloom and Winestock, 1995; recruited to the IL-10R(cid:11) chain, activation of STAT1 Ho et al., 1995; Lai et al., 1996; Weber Nordt et al., and STAT5 may occur through other mechanisms 1996a; Wehinger et al., 1996). (Weber-Nordt et al., 1996b). The two membrane- distal tyrosine molecules in the intracytoplasmic tail Genes induced oftheIL-10R(cid:11)chainandSTAT3areessentialforthe antiproliferative and developmental actions of IL-10, but an additonal C-terminal sequence which contains IL-10 induces expression of Fc(cid:13)RI, TIMP-1 (tissue at least one functionally critical serine residue is inhibitorofmetalloproteinases1),MCP-1,Ilinck(IL- required for the anti-inflammatory effects of IL-10 10-induced chemokine), CCR5 on monocytes, and such as inhibition of TNF(cid:11) production by mono- enhances IL-1Ra and soluble p55 and p75 TNF(cid:11)R. cytes/macrophages(O’Farrelletal.,1998;Rileyetal., On mouse mast cells it induces expression of mast 1999).Anothermembrane-proximalregionoftheIL- cell-specific proteases mMCP-1 and mMCP-2, 10R(cid:11) chain has been implicated as a functional whereas on mouse B cells it enhanced expression of domain involved in regative regulation (Ho et al., MHC class II. On human B cells it enhanced expres- 1995). sion of Bcl-2 and the high-affinity IL-2R. A protein IL-10 antagonizes the induction of some IFN(cid:11)- homologous to SNAP23 (synaptosomal-associated or IFN(cid:13)-inducible genes on human monocytes by protein of 23kDa) was induced by IL-10 in OTT1 preventing the IFN-induced phosphorylation of cells (Morikawa et al., 1998). IL-10 inhibited the IL-10 Receptor 1501 proliferation of bone marrow-derived macrophages birth and developed normally until 12 weeks of age, and of J774 cells by STAT3-dependent induction of at which time a majority developed a chronic colitis the cyclin-dependent kinase inhibitor p19INK4D, and splenomegaly, reminiscent of the pathology and which acts on the interactions between cdk’s 4 and 6 phenotype of IL-10 knockout mice (Spencer et al., andDcyclins,andtheSTAT3-independentinduction 1998). Cells from IL-10R(cid:12)(cid:255)/(cid:255) mice responded of p21CIP1, which has been shown to inhibit cyclins normally to type I and type II interferons, but did A or E-associated cdk-2 activity. not respond to IL-10. Promoter regions involved Human abnormalities IL-10-activatedSTAT1,STAT3,andSTAT5areable No human abnormalities related to the IL-10R to bind to the GRR (IFN(cid:13) response region) of the complex have been described to date. Fc(cid:13)RIgene,theSIE(serum-inducibleelement)ofthe c-fos promoterand the PRL-STAT(prolactin STAT) consensus sequence of the (cid:12)-casein gene (Wehinger THERAPEUTIC UTILITY et al., 1996). In addition, STAT3 bound the IL-6 response element in hepatoma cells transfected with Effect of treatment with soluble the IL-10R (Lai et al., 1996) and could enhance the receptor domain expressionofhsp90(cid:11)(heatshockprotein)andhsp90(cid:12) promoters in these cells and in peripheral blood mononuclear cells (Ripley, 1999). Finally, IL-10 ShIL-10R are able to neutralize the effects of IL-10 activated two STAT3-binding sites in the proximal in proliferation and differentation assays (Tan et al., p19INK4D promoter (O’Farrell et al., 2000). 1995). IL-10 downregulated IFN(cid:13)-induced ICAM1 tran- scription in human monocytes by preventing IFN(cid:13)- Effects of inhibitors (antibodies) induced binding activity at the NF(cid:20)B site of the TNF(cid:11)-responsiveNF(cid:20)B/CEBPcompositeelementin to receptors the ICAM1 promoter (Song et al., 1997). Anti-IL-10R antibodies that neutralize the biological activityofmIL-10orhIL-10havebeendescribed(Ho BIOLOGICAL CONSEQUENCES et al., 1995; Liu et al., 1998). Although in vivo studies OF ACTIVATING OR in mice are ongoing, it can be predicted that anti-IL- INHIBITING RECEPTOR AND 10R monoclonal antibodies, like anti-IL-10 mono- clonal antibodies, are able to enhance acquired PATHOPHYSIOLOGY cellular immune reponses against intracellular patho- gens,bacteria,andtumorcells(DeWaalMalefytand Unique biological effects of Moore, 1998). activating the receptors References IL-10 binding to its receptor complex induces the modulation of a wide variety of immunological and biologicalresponsesasdescribedintheIL-10chapter. Bovolenta, C., Gasperini, S., McDonald, P. P., and Cassatella, M. A. (1998). High affinity receptor for IgG (Fc However, the most prominent activity of IL-10 is gamma RI/CD64) gene and STAT protein binding to the probably its immunosuppressive and anti-inflamma- IFN-gammaresponseregion(GRR)areregulateddifferentially tory actions on monocytes (De Waal Malefyt and inhumanneutrophilsandmonocytesbyIL-10.J.Immunol.160, Moore, 1998). 911–919. Cassatella, M. A., Gasperini, S., Bovolenta, C., Calzetti, F., Vollebregt, M., Scapini, P., Marchi, M., Suzuki, R., Phenotypes of receptor knockouts Suzuki, A., and Yoshimura, A. (1999). Interleukin-10 (IL-10) selectivelyenhancesCIS3/SOCS3mRNAexpressioninhuman and receptor overexpression mice neutrophils: evidence for an IL-10-induced pathway that is independentofSTATproteinactivation.Blood94,2880–2889. DeWaalMalefyt,R.,andMoore,K.W.(1998).In‘‘TheCytokine An IL-10R(cid:12) chain knockout mouse has been Handbook,3rdedn’’(edA.Thomson),Interleukin-10,pp.333– described. These mice did not show abnormalities at 364.AcademicPress,London. 1502 Rene de Waal Malefyt Denning, T. L., Campbell, N. A., Song, F., Garofalo, R. P., O’Farrell,A.-M.,Parry,D.A.,Zindy,F.,Roussel,M.F.,Lees,E., Klimpel, G. R., Reyes, V. E., and Ernst, P. B. (2000). Moore, K. W., and Mui, A. L.-F. (2000). Stat3-dependent Expression of IL-10 receptors on epithelial cells from the induction of p19INK4D by IL-10 contributes to inhibition of murinesmallandlargeintestine.Int.Immunol.12,133–139. macrophageproliferation.J.Immunol.164,4607–4615. Ding,Y.,Qin,L.,Kotenko,S.V.,Pestka,S.,andBromberg,J.S. Reboul,J.,Gardiner,K.,Monneron,D.,Uze,G.,andLutfalla,G. (2000).Asingleaminoaciddeterminestheimmunostimulatory (1999). Comparative genomic analysis of the interferon/inter- activityofinterleukin10.J.Exp.Med.191,213–224. leukin-10receptorgenecluster.GenomeRes.9,242–250. Finbloom,D.S.,andWinestock,K.D.(1995).IL-10inducesthe Riley, J. K., Takeda, K., Akira, S., and Schreiber, R. D. (1999). tyrosinephosphorylationoftyk2andJak1andthedifferential Interleukin-10receptorsignalingthroughtheJAK-STATpath- assembly of STAT1 alpha and STAT3 complexes in human way. Requirement for two distinct receptor-derived signals for Tcellsandmonocytes.JImmunol155,1079–1090. anti-inflammatoryaction.J.Biol.Chem.274,16513–16521. Ho, A. S., Liu, Y., Khan, T. A., Hsu, D. H., Bazan, J. F., and Ripley,B.J.,Stephanou,A.,Isenberg,D.A.,andLatchman,D.S. Moore,K.W.(1993).Areceptorforinterleukin10isrelatedto (1999).Interleukin-10activatesheat-shockprotein90betagene interferon receptors. Proc. Natl Acad. Sci. USA 90, 11267– expression.Immunology97,226–231. 11271. Spencer, S. D., Di Marco, F., Hooley, J., Pitts-Meek, S., Ho,A.S.,Wei,S.H.,Mui,A.L.,Miyajima,A.,andMoore,K.W. Bauer, M., Ryan, A. M., Sordat, B., Gibbs, V. C., and (1995).Functionalregionsofthemouseinterleukin-10receptor Aguet,M.(1998).TheorphanreceptorCRF2–4isanessential cytoplasmicdomain.Mol.CellBiol.15,5043–5053. subunit of the interleukin 10 receptor. J. Exp. Med. 187, 571– Hoover, D. M., Schalk-Hihi, C., Chou, C. C., Menon, S., 578. Wlodawer,A.,andZdanov,A.(1999).Purificationofreceptor Song, S., Ling-Hu, H., Roebuck, K. A., Rabbi, M. F., complexes of interleukin-10 stoichiometry and the importance Donnelly, R. P., and Finnegan, A. (1997). Interleukin-10 ofdeglycosylationintheircrystallization.Eur.J.Biochem.262, inhibits interferon-gamma-induced intercellular adhesion 134–141. molecule-1 gene transcription in human monocytes. Blood 89, Ito,S.,Ansari,P.,Sakatsume,M,Dickensheets,H.,Vazquez,N., 4461–4469. Donnelly, R. P., Larner, A. C., and Finbloom, D. S. (1999). Tan, J. C., Indelicato, S. R., Narula, S. K., Zavodny, P. J., and Interleukin-10inhibitsexpressionofbothinterferonalpha-and Chou,C.C.(1993).Characterizationofinterleukin-10receptors interferongamma-inducedgenesbysuppressingtyrosinephos- onhumanandmousecells.J.Biol.Chem.268,21053–21059. phorylationofSTAT1.Blood93,1456–1463. Tan, J. C., Braun, S., Rong, H., DiGiacomo, R., Dolphin, E., Kotenko, S. V., Krause, C. D., Izotova, L. S., Pollack, B. P., Baldwin, S., Narula, S. K., Zavodny, P. J., and Chou, C. C. Wu, W., and Pestka, S. (1997). Identification and functional (1995). Characterization of recombinant extracellular domain characterizationofasecondchainoftheinterleukin-10receptor of human interleukin-10 receptor. J. Biol. Chem. 270, 12906– complex.EMBOJ.16,5894–5903. 12911. Kotenko,S.V.,Saccani,S.,Izotova,L.S.,Mirochnitchenko,O.V., Weber-Nordt,R.M.,Meraz,M.A.,andSchreiber,R.D.(1994). andPestka,S.(2000).Humancytomegalovirusharborsitsown Lipopolysaccharide-dependent induction of IL-10 receptor uniqueIL-10homolog(cmvIL-10).Proc.NatlAcad.Sci.USA expressiononmurinefibroblasts.J.Immunol.153,3734–3744. 97,1695–700. Weber-Nordt, R. M., Egen, C., Wehinger, J., Ludwig, W., Lai, C. F., Ripperger, J., Morella, K. K., Jurlander, J., Gouilleux-Gruart,V.,Mertelsmann,R.,andFinke,J.(1996a). Hawley, T. S., Carson, W. E., Kordula, T., Caligiuri, M. A., ConstitutiveactivationofSTATproteinsinprimarylymphoid Hawley,R.G.,Fey,G.H.,andBaumann,H.(1996).Receptors and myeloid leukemia cells and in Epstein–Barr virus (EBV)- for interleukin (IL)-10andIL-6-type cytokinesusesimilar sig- relatedlymphomacelllines.Blood88,809–816. naling mechanisms for inducing transcription through IL-6 Weber-Nordt, R. M., Riley, J. K., Greenlund, A. C., responseelements.J.Biol.Chem.271,13968–13975. Moore, K. W., Darnell, J. E., and Schreiber, R. D. (1996b). Liu, Y., Wei, S. H., Ho, A. S., de Waal Malefyt, R., and Stat3 recruitment by two distinct ligand-induced, tyrosine- Moore,K.W.(1994).Expressioncloningandcharacterization phosphorylated docking sites in the interleukin-10 receptor ofahumanIL-10receptor.J.Immunol.152,1821–1829. intracellulardomain.J.Biol.Chem.271,27954–28961. Liu,Y.,deWaalMalefyt,R.,Briere,F.,Parham,C.,Bridon,J.M., Wehinger, J., Gouilleux, F., Groner, B., Finke, J., Banchereau, J., Moore, K. W., and Xu, J. (1997). The EBV Mertelsmann, R., and Weber-Nordt, R. M. (1996). IL-10 IL-10 homologue is a selective agonist with impaired binding induces DNA binding activity of three STAT proteins (Stat1, totheIL-10receptor.J.Immunol.158,604–613. Stat3, and Stat5) and their distinct combinatorial assembly in Michel, G., Mirmohammadsadegh, A., Olasz, E., Jarzebska- thepromotersofselectedgenes.FEBSLett.394,365–370. Deussen, B., Muschen, A., Kemeny, L., Abts, H. F., and Yamaoka,K.,Otsuka,T.,Niiro,H.,Nakashima,H.,Tanaka,Y., Ruzicka, T. (1997). Demonstration and functional analysis of Nagano, S., Ogami, E., Niho, Y., Hamasaki, N., and IL-10receptorsinhumanepidermalcells:decreasedexpression Izuhara, K. (1999). Selective DNA-binding activity of inter- inpsoriaticskin,down-modulationbyIL-8,andup-regulation leukin-10-stimulated STAT molecules in human monocytes. by an antipsoriatic glucocorticosteroid in normal cultured J.InterferonCytokineRes.19,679–685. keratinocytes.J.Immunol.159,6291–6297. Zdanov, A., Schalk-Hihi, C., and Wlodawer, A. (1996). Crystal Morikawa, Y., Nishida, H., Misawa, K., Nosaka, T., structure of human interleukin-10 at 1.6A resolution and a Miyajima, A., Senba, E., and Kitamura, T. (1998). Induction model of a complex with its soluble receptor. Protein Sci. 5, of synaptosomal-associated protein-23kD (SNAP-23) by var- 1955–1962. iouscytokines.Blood92,129–135. Zocchia, C., Spiga, G., Rabin, S. J., Grekova, M., Richert, J., O’Farrell,A.-M.,Liu,Y.,Moore,K.W.,andMui,A.L.(1998). Chernyshev, O., Colton, C., and Mocchetti, I. (1997). IL-10 inhibits macrophage activation and proliferation by Biological activity of interleukin-10 in the central nervous sys- distinct signaling mechanisms: evidence for Stat3-dependent tem.NeurochemInt.30,433–439. and-independentpathways.EMBOJ.17,1006–1018.

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IL-10 Receptor Rene de Waal Malefyt* Department of Molecular Biology, DNAX Research Institute, 901 California Avenue, Palo Alto, CA 94304-1104, USA *corresponding author tel: 650-496-1164, fax: 650-496-1200, e-mail: [email protected] DOI: 10.1006/rwcy.2000.14005. SUMMARY complementation studies in combination with the IL-10R(cid:11) chain (Kotenko et al., 1997). IL-10 interacts with its tetrameric receptor complex consisting of two IL-10R(cid:11) and two IL-10R(cid:12) chains Structure resulting in the phosphorylation and activation of JAK1 and TYK2 kinases, which in turn phosphor- Both IL-10R(cid:11) and IL-10R(cid:12) belong to the class II ylate two tyrosine residues in the intracytoplasmic cytokine receptor family, together with the receptors parts of the IL-10R(cid:11) chains that form docking sites for IFN(cid:11) and IFN(cid:13). Crystallization of human IL-10 for STAT3. Binding of STAT3 results in phosphor- orviralIL-10tosolubleextracellularIL-10R(cid:11)chains ylation by JAK1 and TYK2 kinases, homo- or hasindicatedthatthestoichiometryoftheIL-10/sIL- heterodimerization and translocation to the nucleus 10R(cid:11) complex contains two IL-10 dimers binding to where it binds to the promoters of IL-10-responsive four shIL-10R(cid:11) monomers (Hoover et al., 1999), genes such as the Fc(cid:13)RI and activates transcription. confirming results from previous gel filtration experi- All IL-10-mediated responses are dependent on acti- ments(Tanetal.,1995).AmodelofIL-10complexed vation of STAT3, but the anti-inflammatory actions with its soluble receptor at high resolution, based on of IL-10 require additional sequences in the distal topologicalsimilaritybetweenIL-10andIFN(cid:13) isalso intracytoplasmic part of the IL-10R(cid:11) chain. available (Zdanov et al., 1996). Main activities and BACKGROUND pathophysiological roles Discovery The main activity for the IL-10 receptor is to bind IL-10 and initiate the transduction of a signaling IL-10 mediates its biological effects by interacting cascade,whichleadstothemodificationofbiological withspecificcellsurfacereceptors.TheIL-10receptor responses. There have been no specific pathophysio- complex consists of at least two separate receptor logicalrolesdescribedfortheIL-10receptorcomplex chains, a ligand-binding IL-10R(cid:11) chain and a IL- itself. The association of IL-10 with disease is 10R(cid:12)chain,whichisessentialforsignaltransduction. described in the IL-10 chapter. Radiolabeled IL-10 and FLAG epitope-tagged IL-10 were initially used to detect specific receptors on IL-10-responsive cells and to enrich for cells expres- GENE sing high numbers of receptors (Tan et al., 1993). Expression cloning strategies led to the isolation of Accession numbers cDNAs encoding murine and human IL-10R(cid:11)- binding proteins (Ho et al., 1993; Liu et al., 1994). Subsequently, an orphan class II cytokine receptor Mouse IL-10R(cid:11): L12120 was identified as the IL-10R(cid:12) chain by functional Human IL-10R(cid:11): U00672, NM001558 1496 Rene de Waal Malefyt Mouse IL-10R(cid:12): U53696 level. The first extracellular immunoglobulin-like Human IL-10R(cid:12): NM000628 binding domain of the hIL-10R(cid:11) lacks the intracel- lular disulfide bridge and the intracytoplasmic tail lacks one tyrosine residue as compared to the mIL-10R(cid:11), although neither of these differences Sequence seem functionally significant. See Figure 1. Affinity for ligand(s) Mouse and human IL-10 receptor complexes bind Chromosome location and linkages their ligand with high affinity (K (cid:24)35–200pM). d Human IL-10 interacts with mIL-10R complex, but Mouse IL-10R(cid:11): 9 mouse IL-10 does not bind to the hIL-10R complex, Human IL-10R(cid:11): 11q23.3 which is consistent with the observed species specifi- Mouse IL-10R(cid:12): 16 cities of these cytokines. The affinity and specific Human IL-10R(cid:12): 21q22.1–21q22.2 activity of human IL-10 is (cid:24)10-fold lower on cells The structure of the IL-10R(cid:12) loci is conserved expressing mixed receptor complexes consisting of among human, mouse, and chicken but not in fish hIL-10R(cid:11) and mIL-10R(cid:12) chains as compared to (Reboul et al., 1999). mIL-10R(cid:11)(cid:12) complexes. EBV-derived viral IL-10 (vIL-10) boundhuman and mouse IL-10R(cid:11) transfec- tantswithatleasta1000-foldloweraffinitythantheir corresponding cellular ligand/receptor combinations. PROTEIN However, vIL-10 could activate cells through mIL- 10R or hIL-10R with a specific activity identical to Accession numbers thecellularcytokinedependingonthecelltypeandin agreement with the limited biological spectrum of Mouse IL-10R(cid:11): AAA16156.1 vIL-10 as compared to cellular IL-10. Recently, it Human IL-10R(cid:11): NP001549.1 has been shown that a single amino acid substitution Mouse IL-10R(cid:12): AAC53062 at position 87 (I-A) is responsible for the reduced Human IL-10R(cid:12): NP000619 immunostimulatoryactivityofviralIL-10(Dingetal., 2000). All responses to vIL-10 are dependent on the expression of the IL-10R(cid:11) as indicated by a blocking anti-hIL-10R(cid:11) monoclonal antibody (Liu et al., Description of protein 1997). CmvIL-10, a viral homolog of IL-10 identified in human cytomegalovirus ORF UL111a, also binds The mIL-10R(cid:11) and hIL-10R(cid:11) polypeptides are to the hIL-10R complex and induces signal transduc- composedof576and578aminoacidresiduesrespec- tion events and biological activities (Kotenko et al., tively, whereas mIL-10R(cid:12) and hIL-10R(cid:12) chains 2000).Interestingly,unlikeEBV-derivedvIL-10,which consist of 349 and 325 amino acid residues respec- is 84% homologous to hIL-10, cmvIL-10 displays tively. IL-10R(cid:11) chains are expressed as 90–120kDa only 27% homology to hIL-10. proteinsandIL-10R(cid:12) chainshaveamolecularweight of (cid:24)40kDa. IL-10R(cid:11) chains contain four (mouse) to six (human) N-linked glycosylation sites which Cell types and tissues expressing are used. Positive cells express only a few hundred the receptor receptor complexes per cell. IL-10R(cid:11) chains are expressed on cells of hemato- Relevant homologies and species poietic origin including T cells, B cells, monocytes, macrophages,dendriticcells,NKcells,mastcells,and differences varioushematopoieticprogenitors.Inaddition,tumor cells of hematopoietic origin, such as myeloma cells, Mouse and human IL-10R(cid:11) chains are (cid:24)60% BCLL,microglia,etc.havebeendescribedtoexpress identical and 73% similar. Mouse and human IL- the IL-10R(cid:11) The IL-10R(cid:11) is present on epithelial 10R(cid:12) chains are 69% identical at the amino acid cellsfrommurinesmallandlargeintestine,onhuman IL-10 Receptor 1497 Figure 1 Nucleotide sequences for the mouse and human IL-10R(cid:11) genes and the mouse and human IL-10R(cid:12) genes. Mouse IL-10Ra: 1 CCATTGTGCT GGAAAGCAGG ACGCGCCGGC CGGAGGCGTA AAGGCCGGCT CCAGTGGACG 61 ATGCCGCTGT GCGCCCAGGA TGTTGTCGCG TTTGCTCCCA TTCCTCGTCA CGATCTCCAG 121 CCTGAGCCTA GAATTCATTG CATACGGGAC AGAACTGCCA AGCCCTTCCT ATGTGTGGTT 181 TGAAGCCAGA TTTTTCCAGC ACATCCTCCA CTGGAAACCT ATCCCAAACC AGTCTGAGAG 241 CACCTACTAT GAAGTGGCCC TCAAACAGTA CGGAAACTCA ACCTGGAATG ACATCCATAT 301 CTGTAGAAAG GCTCAGGCAT TGTCCTGTGA TCTCACAACG TTCACCCTGG ATCTGTATCA 361 CCGAAGCTAT GGCTACCGGG CCAGAGTCCG GGCAGTGGAC AACAGTCAGT ACTCCAACTG 421 GACCACCACT GAGACTCGCT TCACAGTGGA TGAAGTGATT CTGACAGTGG ATAGCGTGAC 481 TCTGAAAGCA ATGGACGGCA TCATCTATGG GACAATCCAT CCCCCCAGGC CCACGATAAC 541 CCCTGCAGGG GATGAGTACG AACAAGTCTT CAAGGATCTC CGAGTTTACA AGATTTCCAT 601 CCGGAAGTTC TCAGAACTAA AGAATGCAAC CAAGAGAGTG AAACAGGAAA CCTTCACCCT 661 CACGGTCCCC ATAGGGGTGA GAAAGTTTTG TGTCAAGGTG CTGCCCCGCT TGGAATCCCG 721 AATTAACAAG GCAGAGTGGT CGGAGGAGCA GTGTTTACTT ATCACGACGG AGCAGTATTT 781 CACTGTGACC AACCTGAGCA TCTTAGTCAT ATCTATGCTG CTATTCTGTG GAATCCTGGT 841 CTGTCTGGTT CTCCAGTGGT ACATCCGGCA CCCGGGGAAG TTGCCTACAG TCCTGGTCTT 901 CAAGAAGCCT CACGACTTCT TCCCAGCCAA CCCTCTCTGC CCAGAAACTC CCGATGCCAT 961 TCACATCGTG GACCTGGAGG TTTTCCCAAA GGTGTCACTA GAGCTGAGAG ACTCAGTCCT 1021 GCATGGCAGC ACCGACAGTG GCTTTGGCAG TGGTAAACCA TCACTTCAGA CTGAAGAGTC 1081 CCAATTCCTC CTCCCTGGCT CCCACCCCCA GATACAGGGG ACTCTGGGAA AAGAAGAGTC 1141 TCCAGGGCTA CAGGCCACCT GTGGGGACAA CACGGACAGT GGGATCTGCC TGCAGGAGCC 1201 CGGCTTACAC TCCAGCATGG GGCCCGCCTG GAAGCAGCAG CTTGGATATA CCCATCAGGA 1261 CCAGGATGAC AGTGACGTTA ACCTAGTCCA GAACTCTCCA GGGCAGCCTA AGTACACACA 1321 GGATGCATCT GCCTTGGGCC ATGTCTGTCT CCTAGAACCT AAAGCCCCTG AGGAGAAAGA 1381 CCAAGTCATG GTGACATTCC AGGGCTACCA GAAACAGACC AGATGGAAGG CAGAGGCAGC 1441 AGGCCCAGCA GAATGCTTGG ACGAAGAGAT TCCCTTGACA GATGCCTTTG ATCCTGAACT 1501 TGGGGTACAC CTGCAGGATG ATTTGGCTTG GCCTCCACCA GCTCTGGCCG CAGGTTATTT 1561 GAAACAGGAG TCTCAAGGGA TGGCTTCTGC TCCACCAGGG ACACCAAGTA GACAGTGGAA 1621 TCAACTGACC GAAGAGTGGT CACTCCTGGG TGTGGTTAGC TGTGAAGATC TAAGCATAGA 1681 AAGTTGGAGG TTTGCCCATA AACTTGACCC TCTGGACTGT GGGGCAGCCC CTGGTGGCCT 1741 CCTGGATAGC CTTGGCTCTA ACCTGGTCAC CCTGCCGTTG ATCTCCAGCC TGCAGGTAGA 1801 AGAATGACAG CGGCTAAGAG TTATTTGTAT TCCAGCCATG CCTGCTCCCC TCCCTGTACC 1861 TGGGAGGCTC AGGAGTCAAA GAAATATGTG GGTCCTTTTC TGCAGACCTA CTGTGACCAG 1921 CTAGCCAGGC TCCACGGGGC AAGGAAAGGC CATCTTGATA CACGAGTGTC AGGTACATGA 1981 GAGGTTGTGG CTAGTCTGCT GAGTGAGGGT CTGTAGATAC CAGCAGAGCT GAGCAGGATT 2041 GACAGAGACC TCCTCATGCC TCAGGGCTGG CTCCTACACT GGAAGGACCT GTGTTTGGGT 2101 GTAACCTCAG GGCTTTCTGG ATGTGGTAAG ACTGTAGGTC TGAAGTCAGC TGAGCCTGGA 2161 TGTCTGCGGA GGTGTTGGAG TGGCTAGCCT GCTACAGGAT AAAGGGAAGG CTCAAGAGAT 2221 AGAAGGGCAG AGCATGAGCC AGGTTTAATT TTGTCCTGTA GAGATGGTCC CCAGCCAGGA 2281 TGGGTTACTT GTGGCTGGGA GATCTTGGGG TATACACCAC CCTGAATGAT CAGCCAGTCA 2341 ATTCAGAGCT GTGTGGCAAA AGGGACTGAG ACCCAGAATT TCTGTTCCTC TTGTGAGGTG 2401 TCTCTGCTAC CCATCTGCAG ACAGACATCT TCATCTTTTT ACTATGGCTG TGTCCCCTGA 2461 ATTACCAGCA GTGGCCAAGC CATTACTCCC TGCTGCTCAC TGTTGTGACG TCAGACCAGA 2521 CCAGACGCTG TCTGTCTGTG TTAGTACACT ACCCTTTAGG TGGCCTTTGG GCTTGAGCAC 2581 TGGCCCAGGC TTAGGACTTA TGTCTGCTTT TGCTGCTAAT CTCTAACTGC AGACCCAGAG 2641 AACAGGGTGC TGGGCTGACA CCTCCGTGTT CAGCTGTGTG ACCTCCGACC AGCAGCTTCC 2701 TCAGGGGACT AAAATAATGA CTAGGTCATT CAGAAGTCCC TCATGCTGAA TGTTAACCAA 2761 GGTGCCCCTG GGGTGATAGT TTAGGTCCTG CAACCTCTGG GTTGGAAGGA AGTGGACTAC 2821 GGAAGCCATC TGTCCCCCTG GGGAGCTTCC ACCTCATGCC AGTGTTTCAG AGATCTTGTG 2881 GGAGCCTAGG GCCTTGTGCC AAGGGAGCTG CTAGTCCCTG GGGTCTAGGG CTGGTCCCTG 2941 CCTCCCTATA CTGCGTTTGA GACCTGTCTT CAAATGGAGG CAGTTTGCAG CCCCTAAGCA 3001 AGGATGCTGA GAGAAGCAGC AAGGCTGCTG ATCCCTGAGC CCAGAGTTTC TCTGAAGCTT 3061 TCCAAATACA GACTGTGTGA CGGGGTGAGG CCAGCCATGA ACTTTGGCAT CCTGCCGAGA 3121 AGGTCATGAC CCTAATCTGG TACGAGAGCT CCTTCTGGAA CTGGGCAAGC TCTTTGAGAC 3181 CCCCCTGGAA CCTTTATTTA TTTATTTGCT CACTTATTTA TTGAGGAAGC AGCGTGGCAC 3241 AGGCGCAAGG CTCTGGGTCT CTCAGGAGGT CTAGATTTGC CTGCCCTGTT TCTAGCTGTG 3301 TGACCTTGGG CAAGTCACGT TTCCTCGTGG AGCCTCAGTT TTCCTGTCTG TATGCAAAGC 3361 TTGGAAATTG AAATGTACCT GACGTGCTCC ATCCCTAGGA GTGCTGAGTC CCACTGAGAA 3421 AGCGGGCACA GACGCCTCAA ATGGAACCAC AAGTGGTGTG TGTTTTCATC CTAATAAAAA 3481 GTCAGGTGTT TTGTGGA 1498 Rene de Waal Malefyt Figure 1 (Continued) Human IL-10Ra: 1 AAAGAGCTGG AGGCGCGCAG GCCGGCTCCG CTCCGGCCCC GGACGATGCG GCGCGCCCAG 61 GATGCTGCCG TGCCTCGTAG TGCTGCTGGC GGCGCTCCTC AGCCTCCGTC TTGGCTCAGA 121 CGCTCATGGG ACAGAGCTGC CCAGCCCTCC GTCTGTGTGG TTTGAAGCAG AATTTTTCCA 181 CCACATCCTC CACTGGACAC CCATCCCAAA TCAGTCTGAA AGTACCTGCT ATGAAGTGGC 241 GCTCCTGAGG TATGGAATAG AGTCCTGGAA CTCCATCTCC AACTGTAGCC AGACCCTGTC 301 CTATGACCTT ACCGCAGTGA CCTTGGACCT GTACCACAGC AATGGCTACC GGGCCAGAGT 361 GCGGGCTGTG GACGGCAGCC GGCACTCCAA CTGGACCGTC ACCAACACCC GCTTCTCTGT 421 GGATGAAGTG ACTCTGACAG TTGGCAGTGT GAACCTAGAG ATCCACAATG GCTTCATCCT 481 CGGGAAGATT CAGCTACCCA GGCCCAAGAT GGCCCCCGCG AATGACACAT ATGAAAGCAT 541 CTTCAGTCAC TTCCGAGAGT ATGAGATTGC CATTCGCAAG GTGCCGGGAA ACTTCACGTT 601 CACACACAAG AAAGTAAAAC ATGAAAACTT CAGCCTCCTA ACCTCTGGAG AAGTGGGAGA 661 GTTCTGTGTC CAGGTGAAAC CATCTGTCGC TTCCCGAAGT AACAAGGGGA TGTGGTCTAA 721 AGAGGAGTGC ATCTCCCTCA CCAGGCAGTA TTTCACCGTG ACCAACGTCA TCATCTTCTT 781 TGCCTTTGTC CTGCTGCTCT CCGGAGCCCT CGCCTACTGC CTGGCCCTCC AGCTGTATGT 841 GCGGCGCCGA AAGAAGCTAC CCAGTGTCCT GCTCTTCAAG AAGCCCAGCC CCTTCATCTT 901 CATCAGCCAG CGTCCCTCCC CAGAGACCCA AGACACCATC CACCCGCTTG ATGAGGAGGC 961 CTTTTTGAAG GTGTCCCCAG AGCTGAAGAA CTTGGACCTG CACGGCAGCA CAGACAGTGG 1021 CTTTGGCAGC ACCAAGCCAT CCCTGCAGAC TGAAGAGCCC CAGTTCCTCC TCCCTGACCC 1081 TCACCCCCAG GCTGACAGAA CGCTGGGAAA CGGGGAGCCC CCTGTGCTGG GGGACAGCTG 1141 CAGTAGTGGC AGCAGCAATA GCACAGACAG CGGGATCTGC CTGCAGGAGC CCAGCCTGAG 1201 CCCCAGCACA GGGCCCACCT GGGAGCAACA GGTGGGGAGC AACAGCAGGG GCCAGGATGA 1261 CAGTGGCATT GACTTAGTTC AAAACTCTGA GGGCCGGGCT GGGGACACAC AGGGTGGCTC 1321 GGCCTTGGGC CACCACAGTC CCCCGGAGCC TGAGGTGCCT GGGGAAGAAG ACCCAGCTGC 1381 TGTGGCATTC CAGGGTTACC TGAGGCAGAC CAGATGTGCT GAAGAGAAGG CAACCAAGAC 1441 AGGCTGCCTG GAGGAAGAAT CGCCCTTGAC AGATGGCCTT GGCCCCAAAT TCGGGAGATG 1501 CCTGGTTGAT GAGGCAGGCT TGCATCCACC AGCCCTGGCC AAGGGCTATT TGAAACAGGA 1561 TCCTCTAGAA ATGACTCTGG CTTCCTCAGG GGCCCCAACG GGACAGTGGA ACCAGCCCAC 1621 TGAGGAATGG TCACTCCTGG CCTTGAGCAG CTGCAGTGAC CTGGGAATAT CTGACTGGAG 1681 CTTTGCCCAT GACCTTGCCC CTCTAGGCTG TGTGGCAGCC CCAGGTGGTC TCCTGGGCAG 1741 CTTTAACTCA GACCTGGTCA CCCTGCCCCT CATCTCTAGC CTGCAGTCAA GTGAGTGACT 1801 CGGGCTGAGA GGCTGCTTTT GATTTTAGCC ATGCCTGCTC CTCTGCCTGG ACCAGGAGGA 1861 GGGCCCTGGG GCAGAAGTTA GGCACGAGGC AGTCTGGGCA CTTTTCTGCA AGTCCACTGG 1921 GGCTGGCCCA GCCAGGCTGC AGGGCTGGTC AGGGTGTCTG GGGCAGGAGG AGGCCAACTC 1981 ACTGAACTAG TGCAGGGTAT GTGGGTGGCA CTGACCTGTT CTGTTGACTG GGGCCCTGCA 2041 GACTCTGGCA GAGCTGAGAA GGGCAGGGAC CTTCTCCCTC CTAGGAACTC TTTCCTGTAT 2101 CATAAAGGAT TATTTGCTCA GGGGAACCAT GGGGCTTTCT GGAGTTGTGG TGAGGCCACC 2161 AGGCTGAAGT CAGCTCAGAC CCAGACCTCC CTGCTTAGGC CACTCGAGCA TCAGAGCTTC 2221 CAGCAGGAGG AAGGGCTGTA GGAATGGAAG CTTCAGGGCC TTGCTGCTGG GGTCATTTTT 2281 AGGGGAAAAA GGAGGATATG ATGGTCACAT GGGGAACCTC CCCTCATCGG GCCTCTGGGG 2341 CAGGAAGCTT GTCACTGGAA GATCTTAAGG TATATATTTT CTGGACACTC AAACACATCA 2401 TAATGGATTC ACTGAGGGGA GACAAAGGGA GCCGAGACCC TGGATGGGGC TTCCAGCTCA 2461 GAACCCATCC CTCTGGTGGG TACCTCTGGC ACCCATCTGC AAATATCTCC CTCTCTCCAA 2521 CAAATGGAGT AGCATCCCCC TGGGGCACTT GCTGAGGCCA AGCCACTCAC ATCCTCACTT 2581 TGCTGCCCCA CCATCTTGCT GACAACTTCC AGAGAAGCCA TGGTTTTTTG TATTGGTCAT 2641 AACTCAGCCC TTTGGGCGGC CTCTGGGCTT GGGCACCAGC TCATGCCAGC CCCAGAGGGT 2701 CAGGGTTGGA GGCCTGTGCT TGTGTTTGCT GCTAATGTCC AGCTACAGAC CCAGAGGATA 2761 AGCCACTGGG CACTGGGCTG GGGTCCCTGC CTTGTTGGTG TTCAGCTGTG TGATTTTGGA 2821 CTAGCCACTT GTCAGAGGGC CTCAATCTCC CATCTGTGAA ATAAGGACTC CACCTTTAGG 2881 GGACCCTCCA TGTTTGCTGG GTATTAGCCA AGCTGGTCCT GGGAGAATGC AGATACTGTC 2941 CGTGGACTAC CAAGCTGGCT TGTTTCTTAT GCCAGAGGCT AACAGATCCA ATGGGAGTCC 3001 ATGGTGTCAT GCCAAGACAG TATCAGACAC AGCCCCAGAA GGGGGCATTA TGGGCCCTGC 3061 CTCCCCATAG GCCATTTGGA CTCTGCCTTC AAACAAAGGC AGTTCAGTCC ACAGGCATGG 3121 AAGCTGTGAG GGGACAGGCC TGTGCGTGCC ATCCAGAGTC ATCTCAGCCC TGCCTTTCTC 3181 TGGAGCATTC TGAAAACAGA TATTCTGGCC CAGGGAATCC AGCCATGACC CCCACCCCTC 3241 TGCCAAAGTA CTCTTAGGTG CCAGTCTGGT AACTGAACTC CCTCTGGAGG CAGGCTTGAG 3301 GGAGGATTCC TCAGGGTTCC CTTGAAAGCT TTATTTATTT ATTTTGTTCA TTTATTTATT 3361 GGAGAGGCAG CATTGCACAG TGAAAGAATT CTGGATATCT CAGGAGCCCC GAAATTCTAG 3421 CTCTGACTTT GCTGTTTCCA GTGGTATGAC CTTGGAGAAG TCACTTATCC TCTTGGAGCC 3481 TCAGTTTCCT CATCTGCAGA ATAATGACTG ACTTGTCTAA TTCATAGGGA TGTGAGGTTC 3541 TGCTGAGGAA ATGGGTATGA ATGTGCCTTG AACACAAAGC TCTGTCAATA AGTGATACAT 3601 GTTTTTTATT CCAATAAATT GTCAAGACCA CA IL-10 Receptor 1499 Figure 1 (Continued) Mouse IL-10Rb: 1 ACATGGCCCC GTGCGTGGCG GGCTGGCTGG GTGGCTTCCT TCTGGTGCCA GCTCTAGGAA 61 TGATTCCACC CCCTGAGAAG GTCAGAATGA ATTCAGTTAA TTTCAAGAAC ATTCTACAGT 121 GGGAGGTACC TGCTTTCCCC AAAACGAACC TGACTTTCAC AGCTCAGTAT GAAAGTTACA 181 GGTCTTTCCA AGATCACTGC AAGCGCACTG CCTCGACTCA GTGCGACTTC TCTCATCTTT 241 CTAAATACGG AGACTACACT GTGAGAGTCA GGGCTGAATT GGCGGATGAA CATTCGGAGT 301 GGGTCAATGT CACCTTCTGC CCCGTGGAAG ACACCATCAT TGGACCTCCT GAGATGCAGA 361 TAGAATCCCT TGCTGAGTCT TTACACCTGC GTTTCTCAGC CCCACAAATT GAGAATGAGC 421 CTGAGACGTG GACCTTGAAG AACATTTATG ACTCATGGGC TTACAGAGTG CAATACTGGA 481 AAAATGGGAC TAATGAGAAG TTTCAAGTTG TGTCTCCGTA CGACTCTGAG GTCCTCCGGA 541 ACCTGGAGCC GTGGACAACT TACTGCATTC AAGTTCAAGG GTTTCTTCTC GACCAGAACA 601 GAACAGGAGA GTGGAGTGAA CCCATCTGTG AACGGACAGG CAATGACGAA ATAACCCCTT 661 CCTGGATTGT GGCCATCATC CTCATAGTCT CCGTCCTGGT GGTCTTCCTC TTCCTCCTGG 721 GCTGCTTTGT CGTGCTGTGG CTCATTTATA AGAAGACCAA GCATACCTTC CGTTCTGGGA 781 CGTCTCTTCC ACAGCACCTG AAGGAGTTTC TGGGCCACCC CCATCACAGC ACGTTTCTGC 841 TGTTCTCCTT CCCTCCCCCC GAGGAGGCCG AGGTGTTCGA CAAACTAAGC ATCATCAGCG 901 AAGAGTCTGA AGGCAGCAAG CAGAGTCCTG AAGACAACTG TGCCTCAGAG CCCCCGTCTG 961 ATCCAGGGCC TCGGGAGCTG GAGTCCAAGG ATGAAGCTCC CTCACCTCCA CACGATGACC 1021 CCAAACTGCT CACGTCGACC TCAGAAGTAT GACCAGAGAG CCACCTGAAA AAACTCCAAA 1081 TCTAGAACTT CCTGATGCTG CACTGGTACA CACAACCAAA GAGCTAGGTT TTAAACACTC 1141 TACTTGGGAA TTTGCTGCCA TATAAAGACT AATAATTTAG GGACTGAGGG TGTAGCTCAG 1201 TGACTAGAGC TCTTACTTGG CACACATGAA GTCCTAGCTT CGATCCCCAA CACCATATAA 1261 ACCAGGGATG GGGGCACCTA CCTATAAGCC CAGCACTTTG GAGGTAGAGG CAGGAGGATC 1321 ACAGTCATCT TGAACTATAC AGGGAGTTCA AGGCCAAGCT GGACTAGAGA CCCTGTCTAA 1381 GAGAGAGAGA GAGAACTTAT ATATTTTATG GCCACTGAAT GTAATTTGAG CCCTTTGTGC 1441 TCACTAAAAC AAGGATCACA TTTAACTTGT GACAAACAAA AATATTTTAA ATGGGGGGGG 1501 GGGCATGGAA ACACTATGAA ATTATAAGAA TGCCTATAGA CCACCCGCAT CTCAAAAGTG 1561 GTTGGCCCCA TGCGGGACAG ACATGAACAT TTTGGATTCC CAAGGAGCAA AGAGATTTCC 1621 TTCCTTACCT GTGTGTTTTG TATTAATATT AGTGTTCTGT AAATATTCTA Human IL-10Rb: 1 ATGGCGTGGA GTCTTGGGAG CTGGCTGGGT GGCTGCCTGC TGGTGTCAGC ATTGGGAATG 61 GTACCACCTC CCGAAAATGT CAGAATGAAT TCTGTTAATT TCAAGAACAT TCTACAGTGG 121 GAGTCACCTG CTTTTGCCAA AGGGAACCTG ACTTTCACAG CTCAGTACCT AAGTTATAGG 181 ATATTCCAAG ATAAATGCAT GAATACTACC TTGACGGAAT GTGATTTCTC AAGTCTTTCC 241 AAGTATGGTG ACCACACCTT GAGAGTCAGG GCTGAATTTG CAGATGAGCA TTCAGACTGG 301 GTAAACATCA CCTTCTGTCC TGTGGATGAC ACCATTATTG GACCCCCTGG AATGCAAGTA 361 GAAGTACTTG ATGATTCTTT ACATATGCGT TTCTTAGCCC CTAAAATTGA GAATGAATAC 421 GAAACTTGGA CTATGAAGAA TGTGTATAAC TCATGGACTT ATAATGTGCA ATACTGGAAA 481 AACGGTACTG ATGAAAAGTT TCAAATTACT CCCCAGTATG ACTTTGAGGT CCTCAGAAAC 541 CTGGAGCCAT GGACAACTTA TTGTGTTCAA GTTCGAGGGT TTCTTCCTGA TCGGAACAAA 601 GCTGGGGAAT GGAGTGAGCC TGTCTGTGAG CAAACAACCC ATGACGAAAC GGTCCCCTCC 661 TGGATGGTGG CCGTCATCCT CATGGCCTCG GTCTTCATGG TCTGCCTGGC ACTCCTCGGC 721 TGCTTCTCCT TGCTGTGGTG CGTTTACAAG AAGACAAAGT ACGCCTTCTC CCCTAGGAAT 781 TCTCTTCCAC AGCACCTGAA AGAGGTAGGT AGGATGGAGT GA epidermal cells and keratinocytes and can be induced expression of IL-10R(cid:11) mRNA by human T cell on fibroblasts (Michel et al., 1997; Denning et al., clones was downregulated following activation (Liu 2000). et al., 1994). IL-10R(cid:12) chain seems to be expressed ubiquitously. Release of soluble receptors Regulation of receptor expression No data has been published on the production and IL-10R(cid:11) expression is induced in fibroblasts by LPS releaseofsolubleIL-10receptorsinnormalordisease activation(Weber-Nordtetal.,1994).Incontrast,the states. 1500 Rene de Waal Malefyt SIGNAL TRANSDUCTION STAT1 (Ito et al., 1999). This may be mediated by the rapid STAT3-dependent induction of SOCS3 Associated or intrinsic kinases (suppressor of cytokine signaling 3). SOCS proteins are members of a family of molecules that interfere withJAK/STATsignaltransductionpathways.Alter- NeithertheIL-10R(cid:11)northeIL-10R(cid:12)chainpossesses natively, differences in DNA-binding activity and anintrinsickinaseactivity.However,IL-10treatment composition of IL-10-induced STAT1 and IFN- of cells induces phosphorylation of the IL-10R(cid:11)- induced STAT1 complexes may play a role in the associated JAK1 and the IL-10R(cid:12)-associated TYK2 differential responses to IL-10 and IFN(cid:13) (Yamaoka kinases (Finbloom and Winestock, 1995; Ho et al., et al., 1999). 1995). Interestingly, in contrast to IFN(cid:13), IL-10 failed to upregulate Fc(cid:13)RI expression and GRR (IFN(cid:13) response region)- or SIE (serum-inducible element)- Cytoplasmic signaling cascades binding activity in human neutrophils, despite the presenceofafunctionalIL-10Rcomplex,andSTAT1 PhosphorylationofJAK1(Januskinase1)andTYK2 andSTAT3expressionbythesecells(Bovolentaetal., kinases by IL-10 binding to the receptor complex 1998). IL-10 did induce SOCS3 expression in neutro- activates their kinase activity and leads to phosphor- phils, indicating that activation of STAT1 or STAT3 ylation of two tyrosine residues, which are part of phosphorylationis notrequired forSOCS3induction thecytokinereceptorbox3motif,(Y446andY496in in these cells as it is in monocytes (Cassatella et al., hIL-10R(cid:11) and Y427 and Y477 in mIL-10R(cid:11)) in 1999). the intracytoplasmic tail of the IL-10R(cid:11) chain. Othersignalingpathwaysthathavebeenimplicated Phosphorylation of at least one tyrosine residue is in biological responses to IL-10 include NF(cid:20)B, phos- sufficient for a biological response. These phosphor- phatidylinositol 3-kinase, p70 S6 kinase, and MAP ylatedtyrosineresiduesthenserveasdockingsitesfor kinase cascades, but none of these have been directly the latent transcription factor STAT3 (signal trans- linked to molecules that interact with the IL-10 ducer and activator of transcription 3) which in turn receptor (De Waal Malefyt and Moore, 1998). becomes phosphorylated by the activated JAK1 and TYK2kinases.PhosphorylatedSTATmoleculessub- DOWNSTREAM GENE sequently form homo- or heterodimers and translo- cate from the cytoplasm to the nucleus, where they ACTIVATION bind with high affinity to STAT-binding elements (SBE) in the promoters of IL-10-responsive genes Transcription factors activated (Laietal.,1996;Wehingeretal.,1996).IL-10canalso activate STAT5 and/or only STAT1 DNA-binding IL-10 activates STAT1, STAT3, and in some cell activityinsomecelltypes(Weber-Nordtetal.,1996a; types STAT5 DNA-binding activity and transcrip- Zocchia et al., 1997). Whereas STAT3 is directly tional activation (Finbloom and Winestock, 1995; recruited to the IL-10R(cid:11) chain, activation of STAT1 Ho et al., 1995; Lai et al., 1996; Weber Nordt et al., and STAT5 may occur through other mechanisms 1996a; Wehinger et al., 1996). (Weber-Nordt et al., 1996b). The two membrane- distal tyrosine molecules in the intracytoplasmic tail Genes induced oftheIL-10R(cid:11)chainandSTAT3areessentialforthe antiproliferative and developmental actions of IL-10, but an additonal C-terminal sequence which contains IL-10 induces expression of Fc(cid:13)RI, TIMP-1 (tissue at least one functionally critical serine residue is inhibitorofmetalloproteinases1),MCP-1,Ilinck(IL- required for the anti-inflammatory effects of IL-10 10-induced chemokine), CCR5 on monocytes, and such as inhibition of TNF(cid:11) production by mono- enhances IL-1Ra and soluble p55 and p75 TNF(cid:11)R. cytes/macrophages(O’Farrelletal.,1998;Rileyetal., On mouse mast cells it induces expression of mast 1999).Anothermembrane-proximalregionoftheIL- cell-specific proteases mMCP-1 and mMCP-2, 10R(cid:11) chain has been implicated as a functional whereas on mouse B cells it enhanced expression of domain involved in regative regulation (Ho et al., MHC class II. On human B cells it enhanced expres- 1995). sion of Bcl-2 and the high-affinity IL-2R. A protein IL-10 antagonizes the induction of some IFN(cid:11)- homologous to SNAP23 (synaptosomal-associated or IFN(cid:13)-inducible genes on human monocytes by protein of 23kDa) was induced by IL-10 in OTT1 preventing the IFN-induced phosphorylation of cells (Morikawa et al., 1998). IL-10 inhibited the IL-10 Receptor 1501 proliferation of bone marrow-derived macrophages birth and developed normally until 12 weeks of age, and of J774 cells by STAT3-dependent induction of at which time a majority developed a chronic colitis the cyclin-dependent kinase inhibitor p19INK4D, and splenomegaly, reminiscent of the pathology and which acts on the interactions between cdk’s 4 and 6 phenotype of IL-10 knockout mice (Spencer et al., andDcyclins,andtheSTAT3-independentinduction 1998). Cells from IL-10R(cid:12)(cid:255)/(cid:255) mice responded of p21CIP1, which has been shown to inhibit cyclins normally to type I and type II interferons, but did A or E-associated cdk-2 activity. not respond to IL-10. Promoter regions involved Human abnormalities IL-10-activatedSTAT1,STAT3,andSTAT5areable No human abnormalities related to the IL-10R to bind to the GRR (IFN(cid:13) response region) of the complex have been described to date. Fc(cid:13)RIgene,theSIE(serum-inducibleelement)ofthe c-fos promoterand the PRL-STAT(prolactin STAT) consensus sequence of the (cid:12)-casein gene (Wehinger THERAPEUTIC UTILITY et al., 1996). In addition, STAT3 bound the IL-6 response element in hepatoma cells transfected with Effect of treatment with soluble the IL-10R (Lai et al., 1996) and could enhance the receptor domain expressionofhsp90(cid:11)(heatshockprotein)andhsp90(cid:12) promoters in these cells and in peripheral blood mononuclear cells (Ripley, 1999). Finally, IL-10 ShIL-10R are able to neutralize the effects of IL-10 activated two STAT3-binding sites in the proximal in proliferation and differentation assays (Tan et al., p19INK4D promoter (O’Farrell et al., 2000). 1995). IL-10 downregulated IFN(cid:13)-induced ICAM1 tran- scription in human monocytes by preventing IFN(cid:13)- Effects of inhibitors (antibodies) induced binding activity at the NF(cid:20)B site of the TNF(cid:11)-responsiveNF(cid:20)B/CEBPcompositeelementin to receptors the ICAM1 promoter (Song et al., 1997). Anti-IL-10R antibodies that neutralize the biological activityofmIL-10orhIL-10havebeendescribed(Ho BIOLOGICAL CONSEQUENCES et al., 1995; Liu et al., 1998). Although in vivo studies OF ACTIVATING OR in mice are ongoing, it can be predicted that anti-IL- INHIBITING RECEPTOR AND 10R monoclonal antibodies, like anti-IL-10 mono- clonal antibodies, are able to enhance acquired PATHOPHYSIOLOGY cellular immune reponses against intracellular patho- gens,bacteria,andtumorcells(DeWaalMalefytand Unique biological effects of Moore, 1998). activating the receptors References IL-10 binding to its receptor complex induces the modulation of a wide variety of immunological and biologicalresponsesasdescribedintheIL-10chapter. Bovolenta, C., Gasperini, S., McDonald, P. P., and Cassatella, M. A. (1998). High affinity receptor for IgG (Fc However, the most prominent activity of IL-10 is gamma RI/CD64) gene and STAT protein binding to the probably its immunosuppressive and anti-inflamma- IFN-gammaresponseregion(GRR)areregulateddifferentially tory actions on monocytes (De Waal Malefyt and inhumanneutrophilsandmonocytesbyIL-10.J.Immunol.160, Moore, 1998). 911–919. Cassatella, M. A., Gasperini, S., Bovolenta, C., Calzetti, F., Vollebregt, M., Scapini, P., Marchi, M., Suzuki, R., Phenotypes of receptor knockouts Suzuki, A., and Yoshimura, A. (1999). Interleukin-10 (IL-10) selectivelyenhancesCIS3/SOCS3mRNAexpressioninhuman and receptor overexpression mice neutrophils: evidence for an IL-10-induced pathway that is independentofSTATproteinactivation.Blood94,2880–2889. DeWaalMalefyt,R.,andMoore,K.W.(1998).In‘‘TheCytokine An IL-10R(cid:12) chain knockout mouse has been Handbook,3rdedn’’(edA.Thomson),Interleukin-10,pp.333– described. These mice did not show abnormalities at 364.AcademicPress,London. 1502 Rene de Waal Malefyt Denning, T. L., Campbell, N. A., Song, F., Garofalo, R. P., O’Farrell,A.-M.,Parry,D.A.,Zindy,F.,Roussel,M.F.,Lees,E., Klimpel, G. R., Reyes, V. E., and Ernst, P. B. (2000). Moore, K. W., and Mui, A. L.-F. (2000). Stat3-dependent Expression of IL-10 receptors on epithelial cells from the induction of p19INK4D by IL-10 contributes to inhibition of murinesmallandlargeintestine.Int.Immunol.12,133–139. macrophageproliferation.J.Immunol.164,4607–4615. Ding,Y.,Qin,L.,Kotenko,S.V.,Pestka,S.,andBromberg,J.S. Reboul,J.,Gardiner,K.,Monneron,D.,Uze,G.,andLutfalla,G. (2000).Asingleaminoaciddeterminestheimmunostimulatory (1999). Comparative genomic analysis of the interferon/inter- activityofinterleukin10.J.Exp.Med.191,213–224. leukin-10receptorgenecluster.GenomeRes.9,242–250. Finbloom,D.S.,andWinestock,K.D.(1995).IL-10inducesthe Riley, J. K., Takeda, K., Akira, S., and Schreiber, R. D. (1999). tyrosinephosphorylationoftyk2andJak1andthedifferential Interleukin-10receptorsignalingthroughtheJAK-STATpath- assembly of STAT1 alpha and STAT3 complexes in human way. Requirement for two distinct receptor-derived signals for Tcellsandmonocytes.JImmunol155,1079–1090. anti-inflammatoryaction.J.Biol.Chem.274,16513–16521. Ho, A. S., Liu, Y., Khan, T. A., Hsu, D. H., Bazan, J. F., and Ripley,B.J.,Stephanou,A.,Isenberg,D.A.,andLatchman,D.S. Moore,K.W.(1993).Areceptorforinterleukin10isrelatedto (1999).Interleukin-10activatesheat-shockprotein90betagene interferon receptors. Proc. Natl Acad. Sci. USA 90, 11267– expression.Immunology97,226–231. 11271. Spencer, S. D., Di Marco, F., Hooley, J., Pitts-Meek, S., Ho,A.S.,Wei,S.H.,Mui,A.L.,Miyajima,A.,andMoore,K.W. Bauer, M., Ryan, A. M., Sordat, B., Gibbs, V. C., and (1995).Functionalregionsofthemouseinterleukin-10receptor Aguet,M.(1998).TheorphanreceptorCRF2–4isanessential cytoplasmicdomain.Mol.CellBiol.15,5043–5053. subunit of the interleukin 10 receptor. J. Exp. Med. 187, 571– Hoover, D. M., Schalk-Hihi, C., Chou, C. C., Menon, S., 578. Wlodawer,A.,andZdanov,A.(1999).Purificationofreceptor Song, S., Ling-Hu, H., Roebuck, K. A., Rabbi, M. F., complexes of interleukin-10 stoichiometry and the importance Donnelly, R. P., and Finnegan, A. (1997). Interleukin-10 ofdeglycosylationintheircrystallization.Eur.J.Biochem.262, inhibits interferon-gamma-induced intercellular adhesion 134–141. molecule-1 gene transcription in human monocytes. Blood 89, Ito,S.,Ansari,P.,Sakatsume,M,Dickensheets,H.,Vazquez,N., 4461–4469. Donnelly, R. P., Larner, A. C., and Finbloom, D. S. (1999). Tan, J. C., Indelicato, S. R., Narula, S. K., Zavodny, P. J., and Interleukin-10inhibitsexpressionofbothinterferonalpha-and Chou,C.C.(1993).Characterizationofinterleukin-10receptors interferongamma-inducedgenesbysuppressingtyrosinephos- onhumanandmousecells.J.Biol.Chem.268,21053–21059. phorylationofSTAT1.Blood93,1456–1463. Tan, J. C., Braun, S., Rong, H., DiGiacomo, R., Dolphin, E., Kotenko, S. V., Krause, C. D., Izotova, L. S., Pollack, B. P., Baldwin, S., Narula, S. K., Zavodny, P. J., and Chou, C. C. Wu, W., and Pestka, S. (1997). Identification and functional (1995). Characterization of recombinant extracellular domain characterizationofasecondchainoftheinterleukin-10receptor of human interleukin-10 receptor. J. Biol. Chem. 270, 12906– complex.EMBOJ.16,5894–5903. 12911. Kotenko,S.V.,Saccani,S.,Izotova,L.S.,Mirochnitchenko,O.V., Weber-Nordt,R.M.,Meraz,M.A.,andSchreiber,R.D.(1994). andPestka,S.(2000).Humancytomegalovirusharborsitsown Lipopolysaccharide-dependent induction of IL-10 receptor uniqueIL-10homolog(cmvIL-10).Proc.NatlAcad.Sci.USA expressiononmurinefibroblasts.J.Immunol.153,3734–3744. 97,1695–700. Weber-Nordt, R. M., Egen, C., Wehinger, J., Ludwig, W., Lai, C. F., Ripperger, J., Morella, K. K., Jurlander, J., Gouilleux-Gruart,V.,Mertelsmann,R.,andFinke,J.(1996a). Hawley, T. S., Carson, W. E., Kordula, T., Caligiuri, M. A., ConstitutiveactivationofSTATproteinsinprimarylymphoid Hawley,R.G.,Fey,G.H.,andBaumann,H.(1996).Receptors and myeloid leukemia cells and in Epstein–Barr virus (EBV)- for interleukin (IL)-10andIL-6-type cytokinesusesimilar sig- relatedlymphomacelllines.Blood88,809–816. naling mechanisms for inducing transcription through IL-6 Weber-Nordt, R. M., Riley, J. K., Greenlund, A. C., responseelements.J.Biol.Chem.271,13968–13975. Moore, K. W., Darnell, J. E., and Schreiber, R. D. (1996b). Liu, Y., Wei, S. H., Ho, A. S., de Waal Malefyt, R., and Stat3 recruitment by two distinct ligand-induced, tyrosine- Moore,K.W.(1994).Expressioncloningandcharacterization phosphorylated docking sites in the interleukin-10 receptor ofahumanIL-10receptor.J.Immunol.152,1821–1829. intracellulardomain.J.Biol.Chem.271,27954–28961. Liu,Y.,deWaalMalefyt,R.,Briere,F.,Parham,C.,Bridon,J.M., Wehinger, J., Gouilleux, F., Groner, B., Finke, J., Banchereau, J., Moore, K. W., and Xu, J. (1997). The EBV Mertelsmann, R., and Weber-Nordt, R. M. (1996). IL-10 IL-10 homologue is a selective agonist with impaired binding induces DNA binding activity of three STAT proteins (Stat1, totheIL-10receptor.J.Immunol.158,604–613. Stat3, and Stat5) and their distinct combinatorial assembly in Michel, G., Mirmohammadsadegh, A., Olasz, E., Jarzebska- thepromotersofselectedgenes.FEBSLett.394,365–370. Deussen, B., Muschen, A., Kemeny, L., Abts, H. F., and Yamaoka,K.,Otsuka,T.,Niiro,H.,Nakashima,H.,Tanaka,Y., Ruzicka, T. (1997). Demonstration and functional analysis of Nagano, S., Ogami, E., Niho, Y., Hamasaki, N., and IL-10receptorsinhumanepidermalcells:decreasedexpression Izuhara, K. (1999). Selective DNA-binding activity of inter- inpsoriaticskin,down-modulationbyIL-8,andup-regulation leukin-10-stimulated STAT molecules in human monocytes. by an antipsoriatic glucocorticosteroid in normal cultured J.InterferonCytokineRes.19,679–685. keratinocytes.J.Immunol.159,6291–6297. Zdanov, A., Schalk-Hihi, C., and Wlodawer, A. (1996). Crystal Morikawa, Y., Nishida, H., Misawa, K., Nosaka, T., structure of human interleukin-10 at 1.6A resolution and a Miyajima, A., Senba, E., and Kitamura, T. (1998). Induction model of a complex with its soluble receptor. Protein Sci. 5, of synaptosomal-associated protein-23kD (SNAP-23) by var- 1955–1962. iouscytokines.Blood92,129–135. Zocchia, C., Spiga, G., Rabin, S. J., Grekova, M., Richert, J., O’Farrell,A.-M.,Liu,Y.,Moore,K.W.,andMui,A.L.(1998). Chernyshev, O., Colton, C., and Mocchetti, I. (1997). IL-10 inhibits macrophage activation and proliferation by Biological activity of interleukin-10 in the central nervous sys- distinct signaling mechanisms: evidence for Stat3-dependent tem.NeurochemInt.30,433–439. and-independentpathways.EMBOJ.17,1006–1018.

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