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IL-13 Receptor David J. Matthews and Andrew N.J. McKenzie* MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 2QH, UK *corresponding author tel: 44 1223 402377, fax: 44 1223 412178, e-mail: [email protected] DOI: 10.1006/rwcy.2000.14007. SUMMARY receptor (the type II IL-4 receptor) (Callard et al., 1996). The relationship between the IL-13R(cid:11)1 and There are two membrane-bound IL-13-binding pro- IL-13R(cid:11)2 is not clear but there is evidence that IL- teins, IL-13R(cid:11)1 and IL-13R(cid:11)2. The IL-13R(cid:11)1 pro- 13R(cid:11)2mayactasan IL-13antagonist. The(cid:13)c chain, teinhasamoderateaffinityforIL-13butrequiresthe the promiscuous receptor chain found in the IL-2, presence of IL-4R(cid:11) (CD124) to form a high-affinity IL-4,IL-7,IL-9,andIL-15receptors,doesnotappear receptorcomplex.IL-4R(cid:11)alonedoesnotbindIL-13. to be a functional component of the IL-13 receptor Signaling through the IL-13R(cid:11)1/IL-4R(cid:11) complex (Matthews et al., 1995). activatesSTAT6andIRS-1/2,andIL-13R(cid:11)1appears to recruit a JAK kinase to the activated receptor. In Alternative names contrast, IL-13R(cid:11)2 alone is a high-affinity receptor for IL-13 but there is little evidence that this protein A number of groups have cloned both IL-13 has signal transduction properties. The function of receptors in humans (Aman et al., 1996; Caput et al., IL-13R(cid:11)2 is still unclear, however, it has been 1996;Milouxetal.,1996;Gauchatetal.,1997)andin proposedthatitmayactasanIL-13antagonist.Both mice. The IL-13R(cid:11)1 has also been termed (cid:13)0 and the receptor chains have a wide tissue distribution, IL-13R(cid:11)2 has also been called IL-13R(cid:11)0. although notably, the IL-13R(cid:11)1 receptor does not appear to be expressed on the surface of T cells. Structure BACKGROUND Both IL-13R(cid:11)1 and IL-13R(cid:11)2 are members of the class I cytokine receptor family and have a similar Discovery structuretotheIL-5R(cid:11)chainandcontainaWSXWS motif.Themainstructuraldifferencebetweenthetwo Two IL-13-binding chains have been identified IL-13 receptors is that the IL-13R(cid:11)1 chain has a following the cloning of IL-13. Using an expression longer intracellular domain than IL-13R(cid:11)2. cloning approach, Caput et al. (1996) identified IL- 13R(cid:11)2, a membrane-bound human protein with a Main activities and high affinity for IL-13 but no apparent capacity for pathophysiological roles signal transduction. In contrast, Hilton et al. (1996) obtainedasecondtypeofIL-13receptorbyscreening a mouse genomic library using redundant oligonu- Signals generated by the IL-13R(cid:11)1/IL-4R(cid:11) recep- cleotides to the WSXWS motif (a conserved motif tor complex promote TH2-driven immunological foundinallclassIcytokinereceptors).Thisapproach responses important in parasitic worm infections and identified IL-13R(cid:11)1, a low-affinity IL-13 binding atopy(McKenzieetal.,1998a,1998b).Inhumans,the chain, that requires the presence of the IL-4R(cid:11) signals generated by the IL-13 receptor promote the chain (CD124) in order to form a high-affinity IL-13 production of IgE (Punnonen et al., 1993) but inhibit receptor. As a consequence, the IL-4R(cid:11)/IL-13R(cid:11)1 the production of TH1 proinflammatory mediators complex was also identified as a functional IL-4 such as TNF(cid:11) (Manna and Aggarwal, 1998). 1512 David J. Matthews and Andrew N.J. McKenzie GENE Human IL-13R(cid:11)2: X95302 Mouse IL-13R(cid:11)2: U65747 Accession numbers Sequence Human IL-13R(cid:11)1: Y09328 Mouse IL-13R(cid:11)1: S80963 See Figure 1. Figure 1 Nucleotide sequences for human and mouse IL-13R(cid:11)1 and IL-13R(cid:11)2. hIL-13Ra 1 1 CGGGTAATTT TTTCAAAGTA AACGCTTCGG GCCCCGCGGG ACACTCAGCT AAGAGCCCGG 61 CCGGGCTCCG AGGCGAGAGG CTGCATGGAG TGGCCGGCGC GGCTCTGCGG GCTGTGGGCG 121 CTGCTGCTCT GCGCCGGCGG CGGGGGCGGG GGCGGGGGCG CCGCGCCTAC GGAAACTCAG 181 CCACCTGTGA CAAATTTGAG TGTCTCTGTT GAAAACCTCT GCACAGTAAT ATGGACATGG 241 AATCCACCCG AGGGAGCCAG CTCAAATTGT AGTCTATGGT ATTTTAGTCA TTTTGGCGAC 301 AAACAAGATA AGAAAATAGC TCCGGAAACT CGTCGTTCAA TAGAAGTACC CCTGAATGAG 361 AGGATTTGTC TGCAAGTGGG GTCCCAGTGT AGCACCAATG AGAGTGAGAA GCCTAGCATT 421 TTGGTTGAAA AATGCATCTC ACCCCCAGAA GGTGATCCTG AGTCTGCTGT GATTGAGCTT 481 CAATGCATTT GGCACAACCT GAGCTACATG AAGTGTTCTT GGCTCCCTGG AAGGAATACC 541 AGTCCCGACA CTAACTATAC TCTCTACTAT TGGCACAGAA GCCTGGAAAA AATTCATCAA 601 TGTGAAAACA TCTTTAGAGA AGGCCAATAC TTTGGTTGTT CCTTTGATCT GACCAAAGTG 661 AAGGATTCCA GTTTTGAACA ACACAGTGTC CAAATAATGG TCAAGGATAA TGCAGGAAAA 721 ATTAAACCAT CCTTCAATAT AGTGCCTTTA ACTTCCCGTG TGAAACCTGA TCCTCCACAT 781 ATTAAAAACC TCTCCTTCCA CAATGATGAC CTATATGTGC AATGGGAGAA TCCACAGAAT 841 TTTATTAGCA GATGCCTATT TTATGAAGTA GAAGTCAATA ACAGCCAAAC TGAGACACAT 901 AATGTTTTCT ACGTCCAAGA GGCTAAATGT GAGAATCCAG AATTTGAGAG AAATGTGGAG 961 AATACATCTT GTTTCATGGT CCCTGGTGTT CTTCCTGATA CTTTGAACAC AGTCAGAATA 1021 AGAGTCAAAA CAAATAAGTT ATGCTATGAG GATGACAAAC TCTGGAGTAA TTGGAGCCAA 1081 GAAATGAGTA TAGGTAAGAA GCGCAATTCC ACACTCTACA TAACCATGTT ACTCATTGTT 1141 CCAGTCATCG TCGCAGATGC AATCATAGTA CTCCTGCTTT ACCTAAAAAG GCTCAAGATT 1201 ATTATATTCC CTCCAATTCC TGATCCTGGC AAGATTTTTA AAGAAATGTT TGGAGACCAG 1261 AATGATGATA CTCTGCACTG GAAGAAGTAC GACATCTATG AGAAGCAAAC CAAGGAGGAA 1321 ACCGACTCTG TAGTGCTGAT AGAAAACCTG AAGAAAGCCT CTCAGTGATG GAGATAATTT 1381 ATTTTTACCT TCACTGTGAC CTTGAGAAGA TTCTTCCCAT TCTCCATTTG TTATCTGGGA 1441 ACTTATTAGA TGGAAACTGA AACTACTGCA CCATTTAAAA ACAGGCAGCT CATAAGAGCC 1501 ACAGGTCTTT ATGTTGAGTC GCTAGCAAGA ACAAGAAAAG TTTTAAAGAA AGATGTTGCT 1561 TACTATGAGT GG hIL-13Ra 2 1 GTAAGAACAC TCTCGTGAGT CTAACGGTCT TCCGGATGAA GGCTATTTGA AGTCGCCATA 61 ACCTGGTCAG AAGTGTGCCT GTCGGCGGGG AGAGAGGCAA TATCAAGGTT TTAAATCTCG 121 GAGAAATGGC TTTCGTTTGC TTGGCTATCG GATGCTTATA TACCTTTCTG ATAAGCACAA 181 CATTTGGCTG TACTTCATCT TCAGACACCG AGATAAAAGT TAACCCTCCT CAGGATTTTG 241 AGATAGTGGA TCCCGGATAC TTAGGTTATC TCTATTTGCA ATGGCAACCC CCACTGTCTC 301 TGGATCATTT TAAGGAATGC ACAGTGGAAT ATGAACTAAA ATACCGAAAC ATTGGTAGTG 361 AAACATGGAA GACCATCATT ACTAAGAATC TACATTACAA AGATGGGTTT GATCTTAACA 421 AGGGCATTGA AGCGAAGATA CACACGCTTT TACCATGGCA ATGCACAAAT GGATCAGAAG 481 TTCAAAGTTC CTGGGCAGAA ACTACTTATT GGATATCACC ACAAGGAATT CCAGAAACTA 541 AAGTTCAGGA TATGGATTGC GTATATTACA ATTGGCAATA TTTACTCTGT TCTTGGAAAC 601 CTGGCATAGG TGTACTTCTT GATACCAATT ACAACTTGTT TTACTGGTAT GAGGGCTTGG 661 ATCATGCATT ACAGTGTGTT GATTACATCA AGGCTGATGG ACAAAATATA GGATGCAGAT 721 TTCCCTATTT GGAGGCATCA GACTATAAAG ATTTCTATAT TTGTGTTAAT GGATCATCAG 781 AGAACAAGCC TATCAGATCC AGTTATTTCA CTTTTCAGCT TCAAAATATA GTTAAACCTT 841 TGCCGCCAGT CTATCTTACT TTTACTCGGG AGAGTTCATG TGAAATTAAG CTGAAATGGA 901 GCATACCTTT GGGACCTATT CCAGCAAGGT GTTTTGATTA TGAAATTGAG ATCAGAGAAG 961 ATGATACTAC CTTGGTGACT GCTACAGTTG AAAATGAAAC ATACACCTTG AAAACAACAA 1021 ATGAAACCCG ACAATTATGC TTTGTAGTAA GAAGCAAAGT GAATATTTAT TGCTCAGATG 1081 ACGGAATTTG GAGTGAGTGG AGTGATAAAC AATGCTGGGA AGGTGAAGAC CTATCGAAGA 1141 AAACTTTGCT ACGTTTCTGG CTACCATTTG GTTTCATCTT AATATTAGTT ATATTTGTAA 1201 CCGGTCTGCT TTTGCGTAAG CCAAACACCT ACCCAAAAAT GATTCCAGAA TTTTTCTGTG 1261 ATACATGAAG ACTTTCCATA TCAAGAGACA TGGTATTGAC TCAACAGTTT CCAGTCATGG 1321 CCAAATGTTC AATATGAGTC TCAATAAACT GAATTTTTCT TGCGAATGTT GAAAAA IL-13 Receptor 1513 Figure 1(b) (Contd.) mIL-13Ra 1 1 TGAAAAGATA GAATAAATGG CCTCGTGCCG AATTCGGCAC GAGCCGAGGC GAGGGCCTGC 61 ATGGCGCGGC CAGCGCTGCT GGGCGAGCTG TTGGTGCTGC TACTGTGGAC CGCCACCGTG 121 GGCCAAGTTG CCGCGGCCAC AGAAGTTCAG CCACCTGTGA CGAATTTGAG CGTCTCTGTC 181 GAAAATCTCT GCACGATAAT ATGGACGTGG AGTCCTCCTG AAGGAGCCAG TCCAAATTGC 241 ACTCTCAGAT ATTTTAGTCA CTTTGATGAC CAACAGGATA AGAAAATTGC TCCAGAAACT 301 CATCGTAAAG AGGAATTACC CCTGGATGAG AAAATCTGTC TGCAGGTGGG CTCTCAGTGT 361 AGTGCCAATG AAAGTGAGAA GCCTAGCCCT TTGGTGAAAA AGTGCATCTC ACCCCCTGAA 421 GGTGATCCTG AGTCCGCTGT GACTGAGCTC AAGTGCATTT GGCATAACCT GAGCTATATG 481 AAGTGTTCCT GGCTCCCTGG AAGGAATACA AGCCCTGACA CACACTATAC TCTGTACTAT 541 TGGTACAGCA GCCTGGAGAA AAGTCGTCAA TGTGAAAACA TCTATAGAGA AGGTCAACAC 601 ATTGCTTGTT CCTTTAAATT GACTAAAGTG GAACCTAGTT TTGAACATCA GAACGTTCAA 661 ATAATGGTCA AGGATAATGC TGGGAAAATT AGGCCATCCT GCAAAATAGT GTCTTTAACT 721 TCCTATGTGA AACCTGATCC TCCACATATT AAACATCTTC TCCTCAAAAA TGGTGCCTTA 781 TTAGTGCAGT GGAAGAATCC ACAAAATTTT AGAAGCAGAT GCTTAACTTA TGAAGTGGAG 841 GTCAATAATA CTCAAACCGA CCGACATAAT ATTTTAGAGG TTGAAGAGGA CAAATGCCAG 901 AATTCCGAAT CTGATAGAAA CATGGAGGGT ACAAGTTGTT TCCAACTCCC TGGTGTTCTT 961 GCCGACGCTG TCTACACAGT CAGAGTAAGA GTCAAAACAA ACAAGTTATG CTTTGATGAC 1021 AACAAACTGT GGAGTGATTG GAGTGAAGCA CAGAGTATAG GTAAGGAGCA AAACTCCACC 1081 TTCTACACCA CCATGTTACT CACCATTCCA GTCTTTGTCG CAGTGGCAGT CATAATCCTC 1141 CTTTTTTACC TGAAAAGGCT TAAGATCATT ATATTTCCTC CAATTCCTGA TCCTGGCAAG 1201 ATTTTTAAAG AAATGTTTGG AGACCAGAAT GATGATACCC TGCACTGGAA GAAGTATGAC 1261 ATCTATGAGA AACAATCCAA AGAAGAAACG GATTCTGTAG TGCTGATAGA AAACCTGAAG 1321 AAAGCAGCTC CTTGATGGGG AGAAGTGATT TCTTTCTTGC CTTCAATGTG ACCCTGTGAA 1381 GATTTATTGC ATTCTCCATT TGTTATCTGG GGGACTTGTT AAATAGAAAC TGAAACTACT 1441 CTTGAAAAAC AGGCAGCTCC TAAGAGCCAC AGGTCTTGAT GTGACTTTTG CATTGAAAAC 1501 CCAAACCCAA AGGAGCTCCT TCCAAGAAAA GCAAGAGTTC TTCTCGTTCC TTGTTCCAAT 1561 CCCTAAAAGC AGATGTTTTG CCAAATCCCC AAACTAGAGG ACAAAGACAA GGGGACAATG 1621 ACCATCAATT CATCTAATCA GGAATTGTGA TGGCTTCCTA AGGAATCTCT GCTTGCTCTG mIL-13Ra 2 1 GGCACGAGGG AGAGGAGGAG GGAAAGATAG AAAGAGAGAG AGAAAGATTG CTTGCTACCC 61 CTGAACAGTG ACCTCTCTCA AGACAGTGCT TTGCTCTTCA CGTATAAGGA AGGAAAACAG 121 TAGAGATTCA ATTTAGTGTC TAATGTGGAA AGGAGGACAA AGAGGTCTTG TGATAACTGC 181 CTGTGATAAT ACATTTCTTG AGAAACCATA TTATTGAGTA GAGCTTTCAG CACACTAAAT 241 CCTGGAGAAA TGGCTTTTGT GCATATCAGA TGCTTGTGTT TCATTCTTCT TTGTACAATA 301 ACTGGCTATT CTTTGGAGAT AAAAGTTAAT CCTCCTCAGG ATTTTGAAAT ATTGGATCCT 361 GGATTACTTG GTTATCTCTA TTTGCAATGG AAACCTCCTG TGGTTATAGA AAAATTTAAG 421 GGCTGTACAC TAGAATATGA GTTAAAATAC CGAAATGTTG ATAGCGACAG CTGGAAGACT 481 ATAATTACTA GGAATCTAAT TTACAAGGAT GGGTTTGATC TTAATAAAGG CATTGAAGGA 541 AAGATACGTA CGCATTTGTC AGAGCATTGT ACAAATGGAT CAGAAGTACA AAGTCCATGG 601 ATAGAAGCTT CTTATGGGAT ATCAGATGAA GGAAGTTTGG AAACTAAAAT TCAGGACATG 661 AAGTGTATAT ATTATAACTG GCAGTATTTG GTCTGCTCTT GGAAACCTGG CAAGACAGTA 721 TATTCTGATA CCAACTATAC CATGTTTTTC TGGTATGAGG GCTTGGATCA TGCCTTACAG 781 TGTGCTGATT ACCTCCAGCA TGATGAAAAA AATGTTGGAT GCAAACTGTC CAACTTGGAC 841 TCATCAGACT ATAAAGATTT TTTTATCTGT GTTAATGGAT CTTCAAAGTT GGAACCCATC 901 AGATCCAGCT ATACAGTTTT TCAACTTCAA AATATAGTTA AACCATTGCC ACCAGAATTC 961 CTTCATATTA GTGTGGAGAA TTCCATTGAT ATTAGAATGA AATGGAGCAC ACCTGGAGGA 1021 CCCATTCCAC CAAGGTGTTA CACTTATGAA ATTGTGATCC GAGAAGACGA TATTTCCTGG 1081 GAGTCTGCCA CAGACAAAAA CGATATGAAG TTGAAGAGGA GAGCAAATGA AAGTGAAGAC 1141 CTATGCTTTT TTGTAAGATG TAAGGTCAAT ATATATTGTG CAGATGATGG AATTTGGAGC 1201 GAATGGAGTG AAGAGGAATG TTGGGAAGGT TACACAGGGC CAGACTCAAA GATTATTTTC 1261 ATAGTACCAG TTTGTCTTTT CTTTATATTC CTTTTGTTAC TTCTTTGCCT TATTGTGGAG 1321 AAGGAAGAAC CTGAACCCAC ATTGAGCCTC CATGTGGATC TGAACAAAGA AGTGTGTGCT 1381 TATGAAGATA CCCTCTGTTA AACCACCAAT TTCTTGACAT AGAGCCAGCC AGCAGGAGTC 1441 ATATTAAACT CAATTTCTCT TAAAATTTCG AATACATCTT CTTGAAAATC AGTGTTTGTC 1501 CTAATAGTGT TGGGTTTTTG ACTAAAGTGC TGGATATATA TCTCCAAAAA AAAAAAAAAA 1561 AAAAAAA Chromosome location and linkages chromosome in the region Xq24 (Guo et al., 1997). Both murine genes map to the X chromosome The location of the huIL-13R(cid:11)1 gene is at present (Donaldson et al., 1998). Murine IL-13R(cid:11)1 maps unknown. The huIL-13R(cid:11)2 gene is located on the X to the region DXMit85: 3.8(cid:6)2.1cM (mIL-13R(cid:11)1, 1514 David J. Matthews and Andrew N.J. McKenzie Agtr2) 3.8(cid:6)2.1cM: DXMit49. Murine IL-13R(cid:11)2 Description of protein maps to the region DXMit4: 6.4(cid:6)2.5cM (mIL- 13R(cid:11)2, DXMit34) 7.9(cid:6)2.9cM: DXMit120. BothIL-13R(cid:11)1andIL-13R(cid:11)2proteinscontainanN- terminal immunoglobulin-like domain followed by a class I cytokine receptor region including a WSXWS PROTEIN motif near the transmembrane domain. The human and mouse IL-13R(cid:11)1 proteins have a cytoplasmic regioncapableofsignaltransductionandcontainBox Accession numbers 1 and Box 2 motifs. Although the IL-4R(cid:11) chain has no measurable ability to bind IL-13 (Zurawski et al., Human IL-13R(cid:11)1: P78552 1995), it does, however, act as an affinity converter Mouse IL-13R(cid:11)1: O09030 forIL-13R(cid:11)1,increasingitsaffinityforIL-13by100- Human IL-13R(cid:11)2: Q14627 fold (Hilton et al., 1996). The role of IL-13R(cid:11)2 is Mouse IL-13R(cid:11)2: 3483094 unclear, although it has a very short intracellular domain and it does not appear to be involved in signal transduction. Sequence The IL-13 receptor displays a high degree of complexity in its relationship with its ligands and See Figure 2. with the IL-4 receptor (Callard et al., 1996). IL-13 Figure 2 Amino acid sequences for human and mouse IL-13R(cid:11)1 and IL-13R(cid:11)2. Putative signal peptides are shown in bold. huIL-13Ra 1 1 MEWPARLCGL WALLLCAGGG GGGGGAAPTE TQPPVTNLSV SVENLCTVIW TWNPPEGASS 61 NCSLWYFSHF GDKQDKKIAP ETRRSIEVPL NERICLQVGS QCSTNESEKP SILVEKCISP 121 PEGDPESAVT ELQCIWHNLS YMKCSWLPGR NTSPDTNYTL YYWHRSLEKI HQCENIFREG 181 QYFGCSFDLT KVKDSSFEQH SVQIMVKDNA GKIKPSFNIV PLTSRVKPDP PHIKNLSFHN 241 DDLYVQWENP QNFISRCLFY EVEVNNSQTE THNVFYVQEA KCENPEFERN VENTSCFMVP 301 GVLPDTLNTV RIRVKTNKLC YEDDKLWSNW SQEMSIGKKR NSTLYITMLL IVPVIVAGAI 361 IVLLLYLKRL KIIIFPPIPD PGKIFKEMFG DQNDDTLHWK KYDIYEKQTK EETDSVVLIE 421 NLKKASQ huIL-13Ra 2 1 MAFVCLAIGC LYTFLISTTF GCTSSSDTEI KVNPPQDFEI VDPGYLGYLY LQWQPPLSLD 61 HFKECTVEYE LKYRNIGSET WKTIITKNLH YKDGFDLNKG IEAKIHTLLP WQCTNGSEVQ 121 SSWAETTYWI SPQGIPETKV QDMDCVYYNW QYLLCSWKPG IGVLLDTNYN LFYWYEGLDH 181 ALQCVDYIKA DGQNIGCRFP YLEASDYKDF YICVNGSSEN KPIRSSYFTF QLQNIVKPLP 241 PVYLTFTRES SCEIKLKWSI PLGPIPARCF DYEIEIREDD TTLVTATVEN ETYTLKTTNE 301 TRQLCFVVRS KVNIYCSDDG IWSEWSDKQC WEGEDLSKKT LLRFWLPFGF ILILVIFVTG 361 LLLRKPNTYP KMIPEFFCDT mIL-13Ra 1 1 MARPALLGEL LVLLLWTATV GQVAAATEVQ PPVTNLSVSV ENLCTIIWTW SPPEGASPNC 61 TLRYFSHFDD QQDKKIAPET HRKEELPLDE KICLQVGSQC SANESEKPSP LVKKCISPPE 121 GDPESAVTEL KCIWHNLSYM KCSWLPGRNT SPDTHYTLYY WYSSLEKSRQ CENIYREGQH 181 IACSFKLTKV EPSFEHQNVQ IMVKDNAGKI RPSCKIVSLT SYVKPDPPHI KHLLLKNGAL 241 LVQWKNPQNF RSRCLTYEVE VNNTQTDRHN ILEVEEDKCQ NSESDRNMEG TSCFQLPGVL 301 ADAVYTVRVR VKTNKLCFDD NKLWSDWSEA QSIGKEQNST FYTTMLLTIP VFVAVAVIIL 361 LFYLKRLKII IFPPIPDPGK IFKEMFGDQN DDTLHWKKYD IYEKQSKEET DSVVLIENLK 421 KAAP mIL-13Ra 2 1 MAFVHIRCLC FILLCTITGY SLEIKVNPPQ DFEILDPGLL GYLYLQWKPP VVIEKFKGCT 61 LEYELKYRNV DSDSWKTIIT RNLIYKDGFD LNKGIEGKIR THLSEHCTNG SEVQSPWIEA 121 SYGISDEGSL ETKIQDMKCI YYNWQYLVCS WKPGKTVYSD TNYTMFFWYE GLDHALQCAD 181 YLQHDEKNVG CKLSNLDSSD YKDFFICVNG SSKLEPIRSS YTVFQLQNIV KPLPPEFLHI 241 SVENSIDIRM KWSTPGGPIP PRCYTYEIVI REDDISWESA TDKNDMKLKR RANESEDLCF 301 FVRCKVNIYC ADDGIWSEWS EEECWEGYTG PDSKIIFIVP VCLFFIFLLL LLCLIVEKEE 361 PEPTLSLHVD LNKEVCAYED TLC IL-13 Receptor 1515 and IL-4 can both cross-compete for binding to the Cell types and tissues expressing IL-13 receptor complex (Hilton et al., 1996; Miloux the receptor et al., 1996). In addition, the (cid:13)c, a component of the type 1 IL-4R, appears to compete for the IL-4R(cid:11) See Table 3. chain and inhibit IL-13 binding by sequestering the IL-4R(cid:11) chain (Orchansky et al., 1997; Kuznetsov Regulation of receptor expression and Puri, 1999). This complex relationship may be important in hematopoietic cells where both the type 1 IL-4 receptor and the IL-13 receptors are StudiesonmaturehumanBcellsfoundthatpotentB coexpressed. cell activators, such as the antibodies anti-(cid:22) or anti- CD40, upregulated IL-13R(cid:11)1 mRNA expression, especiallywhentheywereusedtoco-stimulateBcells Relevant homologies and species (Graber et al., 1998; Ogata et al., 1998; Ford et al., differences 1999). In addition, the expression of hIL-13R(cid:11)1 mRNAonhumanperipheralTcells wasshowntobe downregulated after stimulation by either anti-CD3 See Table 1. It is also of note that both human and plus anti-CD28 or anti-CD3 plus PMA (Gauchat mouse IL-13 receptors share approximately 25% et al., 1997). The activation of human monocytes by identity to the IL-5R(cid:11) chain. IL-13 results in the downregulation of IL-13R(cid:11)1 (Graber et al., 1998). Affinity for ligand(s) Release of soluble receptors See Table 2. In humans, soluble IL-13R(cid:11)1 has been detected in T cell supernatants (Graber et al., 1998). In mice, a soluble receptor is present in serum and urine which binds IL-13 with high affinity. Purification and sub- Table1 Percentageofsharedaminoacididentitybetween the IL-13-binding chains sequentpartialsequencingoftheproteinindicatethat it is the soluble form of mIL-13R(cid:11)2 protein (Zhang et al., 1997). huIL- huIL- mIL- mIL- 13R(cid:11)1 13R(cid:11)2 13R(cid:11)1 13R(cid:11)2 SIGNAL TRANSDUCTION huIL-13R(cid:11)1 100% 27% 74% 26% huIL-13R(cid:11)2 27% 100% 25% 59% Associated or intrinsic kinases mIL-13R(cid:11)1 74% 25% 100% 29% mIL-13R(cid:11)2 26% 59% 29% 100% Although the IL-13R(cid:11)1/IL-4R(cid:11) does not have an intrinsic kinase domain, it does associate with Table 2 Summary of the physical properties of the IL-13-binding chains: number of potential glycosylation sites and approximate affinities of IL-13 receptors for IL-13 Human Mouse IL-13R(cid:11)1 IL-13R(cid:11)2 IL-13R(cid:11)1 IL-13R(cid:11)2 sIL-13R(cid:11)2 M 70,000 70,000 60,000 70,000 40,000 r Mature peptide 401aa 354aa 398aa 362aa n.k. Precursor peptide 427aa 380aa 424aa 383aa n.k. Glycosylation sites 10 4 4 4 n.k. Affinity K 4nM 450pM 2–10nM 250pM 35pM d +IL-4R(cid:11) 30pM n.c. 75pM n.c. – n.c.,nochange;n.k.,notknown;sIL-13R(cid:11)2,solubleIL-13R(cid:11)2. 1516 David J. Matthews and Andrew N.J. McKenzie Table 3 Summary of cell types shown to express IL-13 receptor messenger RNA Tissue/cells hIL-13R(cid:11)1 mIL-13R(cid:11)1 hIL-13R(cid:11)2 mIL-13R(cid:11)2 Brain yes not detected yes yes Spleen yes yes yes yes Liver yes yes yes yes Fetal liver yes unknown yes unknown Thymus yes yes yes unknown Heart yes yes yes unknown Lung yes yes yes unknown Kidney yes yes unknown not detected Testis yes yes yes not detected Stomach yes yes yes unknown Skin yes yes yes unknown Appendix yes unknown yes unknown PBC yes unknown yes unknown Bone marrow yes no yes unknown Skeletal muscle yes no yes unknown Colon yes yes unknown unknown Small intestine yes unknown unknown unknown Ovary yes unknown unknown unknown Prostate yes unknown unknown unknown Pancreas yes unknown yes unknown B cells yes unknown yes unknown T cells yes unknown yes unknown Endothelial cells yes unknown yes unknown members of the JAK kinase family. The IL-13 be downregulated by SOCS proteins (Starr et al., receptor hasbeen shown to phosphorylate JAK2 and 1997). In addition, IL-13 also induces the phosphor- TYK2 in fibroblasts (Murata et al., 1998), JAK1, ylation of IRS-1/2 and IL-4R(cid:11) (Keegan et al., 1995) TYK2 in B9 cells (Welham et al., 1995), JAK1 in and activates PI-3 kinase (Wright et al., 1999). In TF-1 cells (Keegan et al., 1995), JAK1, JAK2 and human monocytes, IL-13 has been described as TYK2 in monocytes (Roy and Cathcart, 1998) and inducing cAMPproduction, PLC(cid:13)1 activation,phos- coloncarcinomacelllines(Murataetal.,1996).Partial phoinositol metabolism, and mobilization of intra- deletion analysis of the cytoplasmic domain of IL- cellular calcium stores (Sozzani et al., 1998). The 13R(cid:11)1 cells has noted that the terminal 38 amino tyrosine phosphatase SHP-1 has been implicated in acids were not necessary for proliferation or for the the negative regulation of IL-13 signal transduction tyrosine phosphorylation of JAK1 or TYK2 in FD5 (Haque et al., 1998). cells (Orchansky et al., 1999). There is no evidence that JAK3 kinase is involved in IL-13 signal transduction (Keegan et al., 1995). DOWNSTREAM GENE ACTIVATION Cytoplasmic signaling cascades Transcription factors activated The IL-13R initiates a JAK/STAT signaling cascade resultingintheactivationofSTAT6(Linetal.,1995) STAT6 is activated upon IL-13 receptor activation and STAT3 (Orchansky et al., 1999) and which may and is an important mediator of IL-13 function IL-13 Receptor 1517 (Linetal.,1995;Palmer-Crockeretal.,1996).STAT3 Human abnormalities has also been reported to be activated by IL-13 (Orchansky et al., 1999). The transcription factors There have not been cases described where either c-fos, c-jun, and c-myc have also been shown to be IL-13 receptor has been directly implicated in a upregulated by IL-13 (Doucet et al., 1998). human abnormality; however, in certain cases some polymorphismsintheIL-4R(cid:11)chainhavebeenshown Genes induced to be associated with atopy (Hershey et al., 1997; Mitsuyasu et al., 1998). The IL-13R has been found to be overexpressed and amarker for humangliomas Notable genes induced or upregulated by IL-13 (Debinski et al., 1999a,b). include CD23 (Punnonen et al., 1993), MHC class II, and in human B cells surface IgM (Zurawski and de Vries, 1994). VCAM-1 is found to be upregulated in THERAPEUTIC UTILITY fibroblasts (Doucet et al., 1998) and endothelial cells (Kotowicz et al., 1996). Effect of treatment with soluble receptor domain Promoter regions involved There are no published work describing the effects A STAT6 response element has been described in of using the soluble IL-13 receptor for therapeutic the IL-4 promoter GTCTGATTTCAGGAACAA- purposes in humans. In mice, treatment with a TTTTA (Curiel et al., 1997). recombinant soluble IL-13R(cid:11)2-Fc fusion protein impaired the expulsion of nematode worms (Urban BIOLOGICAL CONSEQUENCES et al., 1998). A soluble form of the mIL-13R(cid:11)1 has OF ACTIVATING OR INHIBITING also been administered to mice and found to increase the production of IgG2a and IgG2b in germinal RECEPTOR AND center B cells (Poudrier et al., 1999). PATHOPHYSIOLOGY Effects of inhibitors (antibodies) to Unique biological effects of receptors activating the receptors There is no published works describing the effects of In humans, only IL-4 and IL-13 have been reported using anti-IL-13 receptor antibodies for therapeutic to induce antibody class-switching to IgE (Punnonen purposes. However, the mutant form of human IL-4, et al., 1993), which is a major mediator of allergic Y124D,isapotentantagonistofbothIL-4andIL-13 responses. Therefore, IL-13 and its receptor are likely (Kruse et al., 1992; Aversa et al., 1993; Matthews to have an important role in the pathology of atopy. et al., 1997) and may have therapeutic potential. Inmice,IL-13hasbeendemonstratedtoplayaunique Some antibodies to the IL-4R(cid:11) chain have been role in inducing the rapid expulsion of certain shown to inhibit B cell responses to both IL-4 and nematode worms, suggesting an important role for IL-13 (Zurawski et al., 1995; Matthews et al., 1997). IL-13 in gut immunology (McKenzie et al., 1998b). Phenotypes of receptor knockouts References and receptor overexpression mice Aman, J., Tayebi, N., Obiri, N., Puri, R., Modi, W., and Leonard, W. (1996). cDNA cloning and characterisation of As yet, neither IL-13R molecules have been knocked the human interleukin 13 receptor (cid:11) chain. J. Biol. Chem. out. However, mice deficient in both the IL-4R(cid:11) 271,29265–29270. chain(Barneretal.,1998)andSTAT6(Takedaetal., Aversa, G., Punnonen, J., Cocks, B., de Waal Malefyt, R., 1996) have been generated and these mice have Vega, F. J., Zurawski, S., Zurawski, G., and de Vries, J. impaired TH2 cell development and fail to expel (1993). An interleukin-4 (IL-4) mutant protein inhibits both IL-4 and IL-13-induced human immunoglobulin G4 (IgG4) nematode infections efficiently (Urban et al., 1998). and IgE synthesis and B cell proliferation: support for a com- These results are in concordance with findings for mon component shared by IL-4 and IL-13 receptors. J. Exp. IL-13-deficient mice (McKenzie et al., 1998b). Med.178,2213–2218. 1518 David J. Matthews and Andrew N.J. McKenzie Barner, M., Mohrs, M., Brombacher, F., and Kopf, M. (1998). Hilton,D.,Zhang,J.-G.,Metcalf,D.,Alexander,W.,Nicola,N., Differences between IL-4R(cid:11)-deficient and IL-4-deficient mice andWilson,T.(1996).Cloningandcharacterisationofabind- reveal a role for IL-13 in the regulation of Th2 responses. ingsubunitoftheinterleukin13receptorthatisalsoacompo- Curr.Biol.8,669–672. nentoftheinterleukin4receptor.Proc.NatlAcad.Sci.USA93, Callard,R.E.,Matthews,D.J.,andHibbert,L.(1996).IL-4and 497–501. IL-13receptors:aretheyoneandthesame?Immunol.Today17, Keegan, A., Johnston, J., Tortolani, P., McReynolds, L., 108–110. Kinzer, C., O’Shea, J., and Paul, W. (1995). Similarities and Caput, D., Laurent, P., Kaghad, M., Lelias, J.-M., Lefort, S., differences in signal transduction by interleukin 4 and inter- Vita, N., and Ferrara, P. (1996). Cloning and characterisation leukin 13: analysis of janus kinase activation. Proc. Natl of a specific interleukin (IL)-13 binding protein structurally Acad.Sci.USA92,7681–7685. related to the IL-5 receptor (cid:11) chain. J. Biol. Chem. 271, Kotowicz, N., Callard, R., Friedrich, K., Matthews, D., and 16921–16926. Klein, N. (1996). Biological activity of IL-4 and IL-13 on Curiel,R.,Lahesmaa,R.,Subleski,J.,Cippitelli,M.,Kirken,R., humanendothelialcells:functionalevidencethatbothcytokines Young, H., and Ghosh, P. (1997). Identification of a Stat6- actthroughthesamereceptor.Int.Immunol.8,1915–1925. responsive element in the promoter of the human interleu- Kruse,N.,Tony,H.,andSebald,W.(1992).Conversionofhuman kin-4gene.Eur.J.Immunol.27,1982–1987. interleukin-4 into a high affinity antagonist by a single amino Debinski, W., Gibo, D. M., Hulet, S. W., Connor, J. R., and acidreplacement.EMBOJ.11,3237–3244. Gillespie,G.Y.(1999a).Receptorforinterleukin13isamarker Kuznetsov,V.A.,andPuri,R.K.(1999).Kineticanalysisofhigh and therapeutic target for human high-grade gliomas. Clin. affinity forms of interleukin (IL)-13 receptors: suppression of CancerRes.5,985–990. IL-13 binding by IL-2 receptor gamma chain. Biophys. J. 77, Debinski, W., Gibo, D. M., Slagle, B., Powers, S. K., and 154–172. Gillespie, G. Y. (1999b). Receptor for interleukin 13 is abun- Lin, J.-X., Migone, T.-S., Tsang, M., Friedmann, M., dantlyandspecificallyover-expressedinpatientswithglioblas- Weatherbee,J.,Zhou,L.,Yamauchi,A.,Bloom,E.,Meitz,J., tomamultiforme.Int.J.Oncol.15,481–486. John,S.,andLeonard,W.(1995).Theroleofsharedreceptor Donaldson, D. D., Whitters, M. J., Fitz, L. J., Neben, T. Y., motifsandcommonStatproteinsinthegenerationofcytokine Finnerty,H.,Henderson,S.L.,O’Hara,R.M.J.,Beier,D.R., pleiotropyandredundancybyIL-2,IL-4,IL-7,IL-13andIL-5. Turner,K.J.,Wood,C.R.,andCollins,M.(1998).Themurine Immunity2,331–339. IL-13receptoralpha2:molecularcloning,characterization,and Manna,S.K.,andAggarwal,B.B.(1998).IL-13suppressesTNF- comparison with murine IL-13 receptor alpha 1. J. Immunol. induced activation of nuclear factor-(cid:20)B, activation protein-1, 161,2317–2324. andapoptosis.J.Immunol.161,2863–2872. Doucet,C.,Brounty-Boye,D.,Pottin-Clemenceau,C.,Jasmin,C., Matthews, D.,Clark, P., Herbert, J., Morgan, G., Armitage, R., Canonica, G. W., and Azzarone, B. (1998). IL-4 and IL-13 Kinnon, C., Minty, A., Grabstein, K., Caput, D., Ferrara, P., specificallyincreaseadhesionmoleculeandinflammatorycyto- and Callard, R. (1995). Function of the interleukin-2 (IL-2) kine expression in human lung fibroblasts. Int. Immunol. 10, receptorgamma-chaininbiologicresponsesofX-linkedsevere 1421–1433. combined immunodeficient B cells to IL-2, IL-4, IL-13 and Ford, D., Sheehan, C., Girasole, C., Priester, R., Kouttab, N., IL-15.Blood85,38–42. Tigges, J., King, T. C., Luciani, A., Morgan, J. W., and Matthews, D. J., Hibbert, L., Friedrich, K., Minty, A., and Maizel, A. L. (1999). The human B cell response to IL-13 is Callard, R. E. (1997). X-SCID B cell responses to interleukin- dependentoncellularphenotypeaswellasmodeofactivation. 4 and interleukin-13 are mediated by a receptor complex that J.Immunol.163,3185–3193. includes the interleukin-4 receptor alpha chain (p140) but not Gauchat, J.-F., Schlagenhauf, E., Feng, N.-P., Moser, R., thegammacchain.Eur.J.Immunol.27,116–121. Yamage, M., Jeanin, P., Alouani, S., Elson, G., McKenzie, G., Bancroft, A., Grencis, R., and Mckenzie, A. Notarangelo,D.,Wells,T.,Eugster,H.-P.,andBonnefoy,J.-Y. (1998a).Adistinct roleforinterleukin-13 in Th2-cell-mediated (1997).Anovel4kbinterleukin-13receptor(cid:11)mRNAexpressed immuneresponses.Curr.Biol.8,339–342. inhumanB,T,andendothelialcellsencodinganalternatetype- McKenzie, G. J., Emson, C. L., Bell, S. E., Anderson, S., II interleukin-4/interleukin-13 receptor. Eur. J. Immunol. 27, Fallon,P.,Zurawski,G.,Murray,R.,andMcKenzie,A.N.J. 971–978. (1998b). Impaired development of Th2 cells in IL-13-deficient Graber, P., Gretener, D., Herren, S., Aubry, J. P., Elson, G., mice.Immunity9,423–432. Poudrier,J.,Lecoanet-Henchoz,S.,Alouani,S.,Losberger,C., Miloux, B., Laurent, P., Bonnin, O., Lupker, J., Caput, D., Bonnefoy, J. Y., Kosco-Vilbois, M. H., and Gauchat, J. F. Vita, N., and Ferrara, P. (1996). Cloning of the human (1998). The distribution of IL-13 receptor (cid:11)1 expression on IL-13R(cid:11)1chainandreconstitutionwiththeIL-4R(cid:11)ofafunc- Bcells,Tcells andmonocytesanditsregulation byIL-13and tionalIL-4/IL-13receptorcomplex.FEBSLett.401,163–166. IL-4.Eur.J.Immunol.28,4286–4298. Mitsuyasu,H.,Izuhara,K.,Mao,X.O.,Gao,P.S.,Arinobu,Y., Guo, J., Apiou, F., Mellerin, M. P., Lebeau, B., Jaques, Y., Enomoto, T., Kawai, M., Saski, S., Dake, Y., Hamasaki, N., and Minvielle, S. (1997). Chromosome mapping and expres- Shirakawa, T., and Hopkin, J. M. (1998). IleVal variant of sion of the human interleukin-13 receptor. Genomics 42, IL4RalphaupregulatesIgEsynthesisandassociateswithatopic 141–145. asthma.Nat.Genet.2,119–120. Haque,S.J.,Harbor,P.,Tabrizi,M.,Yi,T.,andWilliams,B.R. Murata,T.,Noguchi,P.,andPuri,R.(1996).IL-13inducesphos- (1998). Protein-tyrosine phosphatase Shp-1 is a negative regu- phorylation and activation of JAK2 janus kinase in human latorofIL-4-andIL-13-dependentsignaltransduction.J.Biol. colon carcinomacelllines: similarities between IL-4and IL-13 Chem.273,33893–33896. signalling.J.Immunol.156,2972–2978. Hershey,G.K.,Friedrich,M.F.,Esswein,L.A.,Thomas,M.L., Murata,T.,Husain,S.R.,Mohri,H.,andPuri,R.K.(1998).Two andChatila,T.A.(1997).Theassociationofatopywithagain- differentIL-13receptorchainsareexpressedinnormalhuman of-function mutation in the alpha subunit of the interleukin-4 skinfibroblasts,andIL-13mediatesignaltransductionthrough receptor.N.Engl.J.Med.337,1720–1725. acommonpathway.Int.Immunol.8,1103–1110. IL-13 Receptor 1519 Ogata,H.,Ford,D.,Kouttab,N.,King,T.C.,Vita,N.,Minty,A., Starr, R., Willson, T., Viney, E., Murray, L., Rayner, J., Stoeckler, J., Morgan, D., Girasole, C., Morgan, W. J., and Jenkins, B., Gonda, T., Alexander, W., Metcalf, D., Maizel,A.L.(1998).Regulationofinterleukin-13receptorcon- Nicola,N.,andHilton,D.(1997).Afamilyofcytokine-induci- stituentsonmaturehumanBlymphocytes.J.Biol.Chem.279, bleinhibitorsofsignalling.Nature387,917–921. 9864–9871. Takeda, K., Kamanaka, M., Tanaka, T., Kishimoto, T., and Orchansky,P.,Ayres,S.,Hilton,D.,andSchraeder,J.(1997).An Akira,S.(1996).ImpairedIL-13-mediatedfunctionsofmacro- interleukin (IL)-13 receptor lacking the cytoplasmic domain phagesinSTAT6-deficientmice.J.Immunol.157,3220–3222. fails to transduce IL-13-induced signals and inhibits responses Urban, J., Noben-Trauth, N., Donaldson, D., Madden, K., toIL-4.J.Biol.Chem.272,22940–22947. Morris, S., Collins, M., and Finkelman, F. (1998). IL-13, Orchansky,P.L.,Kwan,R.,Lee,F.,andSchrader,J.W.(1999). IL-4R and Stat6 are required for the expulsion of the gastro- Characterization of the cytoplasmic domain of interleukin-13 intestinal nematode parasite Nippostrongylus brasiliensis. receptor-alpha.J.Biol.Chem.274,20818–20825. Immunity8,255–264. Palmer-Crocker, R., Hughes, C., and Pober, J. (1996). IL-4 and Welham, M. J., Learmonth, L., Bone, H., and Schrader, J. W. IL-13 activate the JAK2 tyrosine kinase and Stat6 in cultured (1995).Interleukin-13signaltransductioninlymphohemopoie- human vascular endothelial cells through a common pathway ticcells.Similaritiesanddifferencesinsignaltransductionwith thatdoesnotinvolvethe(cid:13)cchain.J.Clin.Invest.98,604–609. interleukin-4andinsulin.J.Biol.Chem.270,12286–12296. Poudrier, J., Graber, P., Herren, S., Gretener, D., Elson, G., Wright, K., Kolios, G., Westwick, J., and Ward, S. G. (1999). Berney, C., Gauchat, J. F., and Kosco-Vilbois, M. H. (1999). Cytokine-inducedapoptosisinepithelialHT-29cellsisindepen- A soluble form of IL-13 receptor alpha 1 promotes IgG2a dent ofnitric oxide formation. Evidence foran interleukin-13- and IgG2b production by murine germinal center B cells. driven phosphatidylinositol 3-kinase-dependent survival J.Immunol.163,1153–1161. mechanism.J.Biol.Chem.274,17193–17201. Punnonen, J., Aversa, G., Cocks, B., Mckenzie, A., Menon, S., Zhang, J., Hilton, D., Willson, T., McFarlane, C., Roberts, B., Zurawski, G., de Waal Malefyt, R., and de Vries, J. (1993). Moritz, R., Simpson, R., Alexander, W., Metcalf, D., and Interleukin-13 induces interleukin-4-independent IgG4 and Nicola,N.(1997).Identification,purificationandcharacterisa- IgE synthesis and CD23 expression by human B-cells. Proc. tion of a soluble interleukin (IL)-13-binding protein. Evidence NatlAcad.Sci.USA90,3730–3734. thatitisdistinctfromtheclonedIL-13receptorandIL-4recep- Roy,B.,andCathcart,M.K.(1998).Inductionof15-lipoxygenase toralphachains.J.Biol.Chem.272,9474–9480. expression by IL-13 requires tyrosine phosphorylation of Zurawski,G.,anddeVries,J.(1994).Interleukin13,aninterleu- JAK2 and TYK2 in human monocytes. J. Biol. Chem. 273, kin4-likecytokinethatactsonmonocytesandB-cellsbutnot 32023–32029. onT-cells.Immunol.Today15,19–26. Sozzani, P., Hasan, L., Seguelas, M. H., Caput, D., Ferrara, P., Zurawski, S., Chomarat, P., Djossou, O., Bidaud, C., Pipy, B., and Cambon, C. (1998). Il-13 induces tyrosine phos- Mckenzie, A., Miossec, P., Banchereau, J., and Zurawski, G. phorylation of phospholipase C gamma-1 following IRS-2 (1995).Theprimarybindingsubunitofthehumaninterleukin-4 association in human monocytes: relationship with the inhibi- receptor is also a component of the interleukin-13 receptor. toryeffectofIL-13onROIproduction.Biochem.Biophy.Res. J.Biol.Chem.270,13869–13878. Commun.244,665–670.

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IL-13 Receptor PDF

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by  Matthews D.J., McKenzie A.N.J.
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IL-13 Receptor David J. Matthews and Andrew N.J. McKenzie* MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 2QH, UK *corresponding author tel: 44 1223 402377, fax: 44 1223 412178, e-mail: [email protected] DOI: 10.1006/rwcy.2000.14007. SUMMARY receptor (the type II IL-4 receptor) (Callard et al., 1996). The relationship between the IL-13R(cid:11)1 and There are two membrane-bound IL-13-binding pro- IL-13R(cid:11)2 is not clear but there is evidence that IL- teins, IL-13R(cid:11)1 and IL-13R(cid:11)2. The IL-13R(cid:11)1 pro- 13R(cid:11)2mayactasan IL-13antagonist. The(cid:13)c chain, teinhasamoderateaffinityforIL-13butrequiresthe the promiscuous receptor chain found in the IL-2, presence of IL-4R(cid:11) (CD124) to form a high-affinity IL-4,IL-7,IL-9,andIL-15receptors,doesnotappear receptorcomplex.IL-4R(cid:11)alonedoesnotbindIL-13. to be a functional component of the IL-13 receptor Signaling through the IL-13R(cid:11)1/IL-4R(cid:11) complex (Matthews et al., 1995). activatesSTAT6andIRS-1/2,andIL-13R(cid:11)1appears to recruit a JAK kinase to the activated receptor. In Alternative names contrast, IL-13R(cid:11)2 alone is a high-affinity receptor for IL-13 but there is little evidence that this protein A number of groups have cloned both IL-13 has signal transduction properties. The function of receptors in humans (Aman et al., 1996; Caput et al., IL-13R(cid:11)2 is still unclear, however, it has been 1996;Milouxetal.,1996;Gauchatetal.,1997)andin proposedthatitmayactasanIL-13antagonist.Both mice. The IL-13R(cid:11)1 has also been termed (cid:13)0 and the receptor chains have a wide tissue distribution, IL-13R(cid:11)2 has also been called IL-13R(cid:11)0. although notably, the IL-13R(cid:11)1 receptor does not appear to be expressed on the surface of T cells. Structure BACKGROUND Both IL-13R(cid:11)1 and IL-13R(cid:11)2 are members of the class I cytokine receptor family and have a similar Discovery structuretotheIL-5R(cid:11)chainandcontainaWSXWS motif.Themainstructuraldifferencebetweenthetwo Two IL-13-binding chains have been identified IL-13 receptors is that the IL-13R(cid:11)1 chain has a following the cloning of IL-13. Using an expression longer intracellular domain than IL-13R(cid:11)2. cloning approach, Caput et al. (1996) identified IL- 13R(cid:11)2, a membrane-bound human protein with a Main activities and high affinity for IL-13 but no apparent capacity for pathophysiological roles signal transduction. In contrast, Hilton et al. (1996) obtainedasecondtypeofIL-13receptorbyscreening a mouse genomic library using redundant oligonu- Signals generated by the IL-13R(cid:11)1/IL-4R(cid:11) recep- cleotides to the WSXWS motif (a conserved motif tor complex promote TH2-driven immunological foundinallclassIcytokinereceptors).Thisapproach responses important in parasitic worm infections and identified IL-13R(cid:11)1, a low-affinity IL-13 binding atopy(McKenzieetal.,1998a,1998b).Inhumans,the chain, that requires the presence of the IL-4R(cid:11) signals generated by the IL-13 receptor promote the chain (CD124) in order to form a high-affinity IL-13 production of IgE (Punnonen et al., 1993) but inhibit receptor. As a consequence, the IL-4R(cid:11)/IL-13R(cid:11)1 the production of TH1 proinflammatory mediators complex was also identified as a functional IL-4 such as TNF(cid:11) (Manna and Aggarwal, 1998). 1512 David J. Matthews and Andrew N.J. McKenzie GENE Human IL-13R(cid:11)2: X95302 Mouse IL-13R(cid:11)2: U65747 Accession numbers Sequence Human IL-13R(cid:11)1: Y09328 Mouse IL-13R(cid:11)1: S80963 See Figure 1. Figure 1 Nucleotide sequences for human and mouse IL-13R(cid:11)1 and IL-13R(cid:11)2. hIL-13Ra 1 1 CGGGTAATTT TTTCAAAGTA AACGCTTCGG GCCCCGCGGG ACACTCAGCT AAGAGCCCGG 61 CCGGGCTCCG AGGCGAGAGG CTGCATGGAG TGGCCGGCGC GGCTCTGCGG GCTGTGGGCG 121 CTGCTGCTCT GCGCCGGCGG CGGGGGCGGG GGCGGGGGCG CCGCGCCTAC GGAAACTCAG 181 CCACCTGTGA CAAATTTGAG TGTCTCTGTT GAAAACCTCT GCACAGTAAT ATGGACATGG 241 AATCCACCCG AGGGAGCCAG CTCAAATTGT AGTCTATGGT ATTTTAGTCA TTTTGGCGAC 301 AAACAAGATA AGAAAATAGC TCCGGAAACT CGTCGTTCAA TAGAAGTACC CCTGAATGAG 361 AGGATTTGTC TGCAAGTGGG GTCCCAGTGT AGCACCAATG AGAGTGAGAA GCCTAGCATT 421 TTGGTTGAAA AATGCATCTC ACCCCCAGAA GGTGATCCTG AGTCTGCTGT GATTGAGCTT 481 CAATGCATTT GGCACAACCT GAGCTACATG AAGTGTTCTT GGCTCCCTGG AAGGAATACC 541 AGTCCCGACA CTAACTATAC TCTCTACTAT TGGCACAGAA GCCTGGAAAA AATTCATCAA 601 TGTGAAAACA TCTTTAGAGA AGGCCAATAC TTTGGTTGTT CCTTTGATCT GACCAAAGTG 661 AAGGATTCCA GTTTTGAACA ACACAGTGTC CAAATAATGG TCAAGGATAA TGCAGGAAAA 721 ATTAAACCAT CCTTCAATAT AGTGCCTTTA ACTTCCCGTG TGAAACCTGA TCCTCCACAT 781 ATTAAAAACC TCTCCTTCCA CAATGATGAC CTATATGTGC AATGGGAGAA TCCACAGAAT 841 TTTATTAGCA GATGCCTATT TTATGAAGTA GAAGTCAATA ACAGCCAAAC TGAGACACAT 901 AATGTTTTCT ACGTCCAAGA GGCTAAATGT GAGAATCCAG AATTTGAGAG AAATGTGGAG 961 AATACATCTT GTTTCATGGT CCCTGGTGTT CTTCCTGATA CTTTGAACAC AGTCAGAATA 1021 AGAGTCAAAA CAAATAAGTT ATGCTATGAG GATGACAAAC TCTGGAGTAA TTGGAGCCAA 1081 GAAATGAGTA TAGGTAAGAA GCGCAATTCC ACACTCTACA TAACCATGTT ACTCATTGTT 1141 CCAGTCATCG TCGCAGATGC AATCATAGTA CTCCTGCTTT ACCTAAAAAG GCTCAAGATT 1201 ATTATATTCC CTCCAATTCC TGATCCTGGC AAGATTTTTA AAGAAATGTT TGGAGACCAG 1261 AATGATGATA CTCTGCACTG GAAGAAGTAC GACATCTATG AGAAGCAAAC CAAGGAGGAA 1321 ACCGACTCTG TAGTGCTGAT AGAAAACCTG AAGAAAGCCT CTCAGTGATG GAGATAATTT 1381 ATTTTTACCT TCACTGTGAC CTTGAGAAGA TTCTTCCCAT TCTCCATTTG TTATCTGGGA 1441 ACTTATTAGA TGGAAACTGA AACTACTGCA CCATTTAAAA ACAGGCAGCT CATAAGAGCC 1501 ACAGGTCTTT ATGTTGAGTC GCTAGCAAGA ACAAGAAAAG TTTTAAAGAA AGATGTTGCT 1561 TACTATGAGT GG hIL-13Ra 2 1 GTAAGAACAC TCTCGTGAGT CTAACGGTCT TCCGGATGAA GGCTATTTGA AGTCGCCATA 61 ACCTGGTCAG AAGTGTGCCT GTCGGCGGGG AGAGAGGCAA TATCAAGGTT TTAAATCTCG 121 GAGAAATGGC TTTCGTTTGC TTGGCTATCG GATGCTTATA TACCTTTCTG ATAAGCACAA 181 CATTTGGCTG TACTTCATCT TCAGACACCG AGATAAAAGT TAACCCTCCT CAGGATTTTG 241 AGATAGTGGA TCCCGGATAC TTAGGTTATC TCTATTTGCA ATGGCAACCC CCACTGTCTC 301 TGGATCATTT TAAGGAATGC ACAGTGGAAT ATGAACTAAA ATACCGAAAC ATTGGTAGTG 361 AAACATGGAA GACCATCATT ACTAAGAATC TACATTACAA AGATGGGTTT GATCTTAACA 421 AGGGCATTGA AGCGAAGATA CACACGCTTT TACCATGGCA ATGCACAAAT GGATCAGAAG 481 TTCAAAGTTC CTGGGCAGAA ACTACTTATT GGATATCACC ACAAGGAATT CCAGAAACTA 541 AAGTTCAGGA TATGGATTGC GTATATTACA ATTGGCAATA TTTACTCTGT TCTTGGAAAC 601 CTGGCATAGG TGTACTTCTT GATACCAATT ACAACTTGTT TTACTGGTAT GAGGGCTTGG 661 ATCATGCATT ACAGTGTGTT GATTACATCA AGGCTGATGG ACAAAATATA GGATGCAGAT 721 TTCCCTATTT GGAGGCATCA GACTATAAAG ATTTCTATAT TTGTGTTAAT GGATCATCAG 781 AGAACAAGCC TATCAGATCC AGTTATTTCA CTTTTCAGCT TCAAAATATA GTTAAACCTT 841 TGCCGCCAGT CTATCTTACT TTTACTCGGG AGAGTTCATG TGAAATTAAG CTGAAATGGA 901 GCATACCTTT GGGACCTATT CCAGCAAGGT GTTTTGATTA TGAAATTGAG ATCAGAGAAG 961 ATGATACTAC CTTGGTGACT GCTACAGTTG AAAATGAAAC ATACACCTTG AAAACAACAA 1021 ATGAAACCCG ACAATTATGC TTTGTAGTAA GAAGCAAAGT GAATATTTAT TGCTCAGATG 1081 ACGGAATTTG GAGTGAGTGG AGTGATAAAC AATGCTGGGA AGGTGAAGAC CTATCGAAGA 1141 AAACTTTGCT ACGTTTCTGG CTACCATTTG GTTTCATCTT AATATTAGTT ATATTTGTAA 1201 CCGGTCTGCT TTTGCGTAAG CCAAACACCT ACCCAAAAAT GATTCCAGAA TTTTTCTGTG 1261 ATACATGAAG ACTTTCCATA TCAAGAGACA TGGTATTGAC TCAACAGTTT CCAGTCATGG 1321 CCAAATGTTC AATATGAGTC TCAATAAACT GAATTTTTCT TGCGAATGTT GAAAAA IL-13 Receptor 1513 Figure 1(b) (Contd.) mIL-13Ra 1 1 TGAAAAGATA GAATAAATGG CCTCGTGCCG AATTCGGCAC GAGCCGAGGC GAGGGCCTGC 61 ATGGCGCGGC CAGCGCTGCT GGGCGAGCTG TTGGTGCTGC TACTGTGGAC CGCCACCGTG 121 GGCCAAGTTG CCGCGGCCAC AGAAGTTCAG CCACCTGTGA CGAATTTGAG CGTCTCTGTC 181 GAAAATCTCT GCACGATAAT ATGGACGTGG AGTCCTCCTG AAGGAGCCAG TCCAAATTGC 241 ACTCTCAGAT ATTTTAGTCA CTTTGATGAC CAACAGGATA AGAAAATTGC TCCAGAAACT 301 CATCGTAAAG AGGAATTACC CCTGGATGAG AAAATCTGTC TGCAGGTGGG CTCTCAGTGT 361 AGTGCCAATG AAAGTGAGAA GCCTAGCCCT TTGGTGAAAA AGTGCATCTC ACCCCCTGAA 421 GGTGATCCTG AGTCCGCTGT GACTGAGCTC AAGTGCATTT GGCATAACCT GAGCTATATG 481 AAGTGTTCCT GGCTCCCTGG AAGGAATACA AGCCCTGACA CACACTATAC TCTGTACTAT 541 TGGTACAGCA GCCTGGAGAA AAGTCGTCAA TGTGAAAACA TCTATAGAGA AGGTCAACAC 601 ATTGCTTGTT CCTTTAAATT GACTAAAGTG GAACCTAGTT TTGAACATCA GAACGTTCAA 661 ATAATGGTCA AGGATAATGC TGGGAAAATT AGGCCATCCT GCAAAATAGT GTCTTTAACT 721 TCCTATGTGA AACCTGATCC TCCACATATT AAACATCTTC TCCTCAAAAA TGGTGCCTTA 781 TTAGTGCAGT GGAAGAATCC ACAAAATTTT AGAAGCAGAT GCTTAACTTA TGAAGTGGAG 841 GTCAATAATA CTCAAACCGA CCGACATAAT ATTTTAGAGG TTGAAGAGGA CAAATGCCAG 901 AATTCCGAAT CTGATAGAAA CATGGAGGGT ACAAGTTGTT TCCAACTCCC TGGTGTTCTT 961 GCCGACGCTG TCTACACAGT CAGAGTAAGA GTCAAAACAA ACAAGTTATG CTTTGATGAC 1021 AACAAACTGT GGAGTGATTG GAGTGAAGCA CAGAGTATAG GTAAGGAGCA AAACTCCACC 1081 TTCTACACCA CCATGTTACT CACCATTCCA GTCTTTGTCG CAGTGGCAGT CATAATCCTC 1141 CTTTTTTACC TGAAAAGGCT TAAGATCATT ATATTTCCTC CAATTCCTGA TCCTGGCAAG 1201 ATTTTTAAAG AAATGTTTGG AGACCAGAAT GATGATACCC TGCACTGGAA GAAGTATGAC 1261 ATCTATGAGA AACAATCCAA AGAAGAAACG GATTCTGTAG TGCTGATAGA AAACCTGAAG 1321 AAAGCAGCTC CTTGATGGGG AGAAGTGATT TCTTTCTTGC CTTCAATGTG ACCCTGTGAA 1381 GATTTATTGC ATTCTCCATT TGTTATCTGG GGGACTTGTT AAATAGAAAC TGAAACTACT 1441 CTTGAAAAAC AGGCAGCTCC TAAGAGCCAC AGGTCTTGAT GTGACTTTTG CATTGAAAAC 1501 CCAAACCCAA AGGAGCTCCT TCCAAGAAAA GCAAGAGTTC TTCTCGTTCC TTGTTCCAAT 1561 CCCTAAAAGC AGATGTTTTG CCAAATCCCC AAACTAGAGG ACAAAGACAA GGGGACAATG 1621 ACCATCAATT CATCTAATCA GGAATTGTGA TGGCTTCCTA AGGAATCTCT GCTTGCTCTG mIL-13Ra 2 1 GGCACGAGGG AGAGGAGGAG GGAAAGATAG AAAGAGAGAG AGAAAGATTG CTTGCTACCC 61 CTGAACAGTG ACCTCTCTCA AGACAGTGCT TTGCTCTTCA CGTATAAGGA AGGAAAACAG 121 TAGAGATTCA ATTTAGTGTC TAATGTGGAA AGGAGGACAA AGAGGTCTTG TGATAACTGC 181 CTGTGATAAT ACATTTCTTG AGAAACCATA TTATTGAGTA GAGCTTTCAG CACACTAAAT 241 CCTGGAGAAA TGGCTTTTGT GCATATCAGA TGCTTGTGTT TCATTCTTCT TTGTACAATA 301 ACTGGCTATT CTTTGGAGAT AAAAGTTAAT CCTCCTCAGG ATTTTGAAAT ATTGGATCCT 361 GGATTACTTG GTTATCTCTA TTTGCAATGG AAACCTCCTG TGGTTATAGA AAAATTTAAG 421 GGCTGTACAC TAGAATATGA GTTAAAATAC CGAAATGTTG ATAGCGACAG CTGGAAGACT 481 ATAATTACTA GGAATCTAAT TTACAAGGAT GGGTTTGATC TTAATAAAGG CATTGAAGGA 541 AAGATACGTA CGCATTTGTC AGAGCATTGT ACAAATGGAT CAGAAGTACA AAGTCCATGG 601 ATAGAAGCTT CTTATGGGAT ATCAGATGAA GGAAGTTTGG AAACTAAAAT TCAGGACATG 661 AAGTGTATAT ATTATAACTG GCAGTATTTG GTCTGCTCTT GGAAACCTGG CAAGACAGTA 721 TATTCTGATA CCAACTATAC CATGTTTTTC TGGTATGAGG GCTTGGATCA TGCCTTACAG 781 TGTGCTGATT ACCTCCAGCA TGATGAAAAA AATGTTGGAT GCAAACTGTC CAACTTGGAC 841 TCATCAGACT ATAAAGATTT TTTTATCTGT GTTAATGGAT CTTCAAAGTT GGAACCCATC 901 AGATCCAGCT ATACAGTTTT TCAACTTCAA AATATAGTTA AACCATTGCC ACCAGAATTC 961 CTTCATATTA GTGTGGAGAA TTCCATTGAT ATTAGAATGA AATGGAGCAC ACCTGGAGGA 1021 CCCATTCCAC CAAGGTGTTA CACTTATGAA ATTGTGATCC GAGAAGACGA TATTTCCTGG 1081 GAGTCTGCCA CAGACAAAAA CGATATGAAG TTGAAGAGGA GAGCAAATGA AAGTGAAGAC 1141 CTATGCTTTT TTGTAAGATG TAAGGTCAAT ATATATTGTG CAGATGATGG AATTTGGAGC 1201 GAATGGAGTG AAGAGGAATG TTGGGAAGGT TACACAGGGC CAGACTCAAA GATTATTTTC 1261 ATAGTACCAG TTTGTCTTTT CTTTATATTC CTTTTGTTAC TTCTTTGCCT TATTGTGGAG 1321 AAGGAAGAAC CTGAACCCAC ATTGAGCCTC CATGTGGATC TGAACAAAGA AGTGTGTGCT 1381 TATGAAGATA CCCTCTGTTA AACCACCAAT TTCTTGACAT AGAGCCAGCC AGCAGGAGTC 1441 ATATTAAACT CAATTTCTCT TAAAATTTCG AATACATCTT CTTGAAAATC AGTGTTTGTC 1501 CTAATAGTGT TGGGTTTTTG ACTAAAGTGC TGGATATATA TCTCCAAAAA AAAAAAAAAA 1561 AAAAAAA Chromosome location and linkages chromosome in the region Xq24 (Guo et al., 1997). Both murine genes map to the X chromosome The location of the huIL-13R(cid:11)1 gene is at present (Donaldson et al., 1998). Murine IL-13R(cid:11)1 maps unknown. The huIL-13R(cid:11)2 gene is located on the X to the region DXMit85: 3.8(cid:6)2.1cM (mIL-13R(cid:11)1, 1514 David J. Matthews and Andrew N.J. McKenzie Agtr2) 3.8(cid:6)2.1cM: DXMit49. Murine IL-13R(cid:11)2 Description of protein maps to the region DXMit4: 6.4(cid:6)2.5cM (mIL- 13R(cid:11)2, DXMit34) 7.9(cid:6)2.9cM: DXMit120. BothIL-13R(cid:11)1andIL-13R(cid:11)2proteinscontainanN- terminal immunoglobulin-like domain followed by a class I cytokine receptor region including a WSXWS PROTEIN motif near the transmembrane domain. The human and mouse IL-13R(cid:11)1 proteins have a cytoplasmic regioncapableofsignaltransductionandcontainBox Accession numbers 1 and Box 2 motifs. Although the IL-4R(cid:11) chain has no measurable ability to bind IL-13 (Zurawski et al., Human IL-13R(cid:11)1: P78552 1995), it does, however, act as an affinity converter Mouse IL-13R(cid:11)1: O09030 forIL-13R(cid:11)1,increasingitsaffinityforIL-13by100- Human IL-13R(cid:11)2: Q14627 fold (Hilton et al., 1996). The role of IL-13R(cid:11)2 is Mouse IL-13R(cid:11)2: 3483094 unclear, although it has a very short intracellular domain and it does not appear to be involved in signal transduction. Sequence The IL-13 receptor displays a high degree of complexity in its relationship with its ligands and See Figure 2. with the IL-4 receptor (Callard et al., 1996). IL-13 Figure 2 Amino acid sequences for human and mouse IL-13R(cid:11)1 and IL-13R(cid:11)2. Putative signal peptides are shown in bold. huIL-13Ra 1 1 MEWPARLCGL WALLLCAGGG GGGGGAAPTE TQPPVTNLSV SVENLCTVIW TWNPPEGASS 61 NCSLWYFSHF GDKQDKKIAP ETRRSIEVPL NERICLQVGS QCSTNESEKP SILVEKCISP 121 PEGDPESAVT ELQCIWHNLS YMKCSWLPGR NTSPDTNYTL YYWHRSLEKI HQCENIFREG 181 QYFGCSFDLT KVKDSSFEQH SVQIMVKDNA GKIKPSFNIV PLTSRVKPDP PHIKNLSFHN 241 DDLYVQWENP QNFISRCLFY EVEVNNSQTE THNVFYVQEA KCENPEFERN VENTSCFMVP 301 GVLPDTLNTV RIRVKTNKLC YEDDKLWSNW SQEMSIGKKR NSTLYITMLL IVPVIVAGAI 361 IVLLLYLKRL KIIIFPPIPD PGKIFKEMFG DQNDDTLHWK KYDIYEKQTK EETDSVVLIE 421 NLKKASQ huIL-13Ra 2 1 MAFVCLAIGC LYTFLISTTF GCTSSSDTEI KVNPPQDFEI VDPGYLGYLY LQWQPPLSLD 61 HFKECTVEYE LKYRNIGSET WKTIITKNLH YKDGFDLNKG IEAKIHTLLP WQCTNGSEVQ 121 SSWAETTYWI SPQGIPETKV QDMDCVYYNW QYLLCSWKPG IGVLLDTNYN LFYWYEGLDH 181 ALQCVDYIKA DGQNIGCRFP YLEASDYKDF YICVNGSSEN KPIRSSYFTF QLQNIVKPLP 241 PVYLTFTRES SCEIKLKWSI PLGPIPARCF DYEIEIREDD TTLVTATVEN ETYTLKTTNE 301 TRQLCFVVRS KVNIYCSDDG IWSEWSDKQC WEGEDLSKKT LLRFWLPFGF ILILVIFVTG 361 LLLRKPNTYP KMIPEFFCDT mIL-13Ra 1 1 MARPALLGEL LVLLLWTATV GQVAAATEVQ PPVTNLSVSV ENLCTIIWTW SPPEGASPNC 61 TLRYFSHFDD QQDKKIAPET HRKEELPLDE KICLQVGSQC SANESEKPSP LVKKCISPPE 121 GDPESAVTEL KCIWHNLSYM KCSWLPGRNT SPDTHYTLYY WYSSLEKSRQ CENIYREGQH 181 IACSFKLTKV EPSFEHQNVQ IMVKDNAGKI RPSCKIVSLT SYVKPDPPHI KHLLLKNGAL 241 LVQWKNPQNF RSRCLTYEVE VNNTQTDRHN ILEVEEDKCQ NSESDRNMEG TSCFQLPGVL 301 ADAVYTVRVR VKTNKLCFDD NKLWSDWSEA QSIGKEQNST FYTTMLLTIP VFVAVAVIIL 361 LFYLKRLKII IFPPIPDPGK IFKEMFGDQN DDTLHWKKYD IYEKQSKEET DSVVLIENLK 421 KAAP mIL-13Ra 2 1 MAFVHIRCLC FILLCTITGY SLEIKVNPPQ DFEILDPGLL GYLYLQWKPP VVIEKFKGCT 61 LEYELKYRNV DSDSWKTIIT RNLIYKDGFD LNKGIEGKIR THLSEHCTNG SEVQSPWIEA 121 SYGISDEGSL ETKIQDMKCI YYNWQYLVCS WKPGKTVYSD TNYTMFFWYE GLDHALQCAD 181 YLQHDEKNVG CKLSNLDSSD YKDFFICVNG SSKLEPIRSS YTVFQLQNIV KPLPPEFLHI 241 SVENSIDIRM KWSTPGGPIP PRCYTYEIVI REDDISWESA TDKNDMKLKR RANESEDLCF 301 FVRCKVNIYC ADDGIWSEWS EEECWEGYTG PDSKIIFIVP VCLFFIFLLL LLCLIVEKEE 361 PEPTLSLHVD LNKEVCAYED TLC IL-13 Receptor 1515 and IL-4 can both cross-compete for binding to the Cell types and tissues expressing IL-13 receptor complex (Hilton et al., 1996; Miloux the receptor et al., 1996). In addition, the (cid:13)c, a component of the type 1 IL-4R, appears to compete for the IL-4R(cid:11) See Table 3. chain and inhibit IL-13 binding by sequestering the IL-4R(cid:11) chain (Orchansky et al., 1997; Kuznetsov Regulation of receptor expression and Puri, 1999). This complex relationship may be important in hematopoietic cells where both the type 1 IL-4 receptor and the IL-13 receptors are StudiesonmaturehumanBcellsfoundthatpotentB coexpressed. cell activators, such as the antibodies anti-(cid:22) or anti- CD40, upregulated IL-13R(cid:11)1 mRNA expression, especiallywhentheywereusedtoco-stimulateBcells Relevant homologies and species (Graber et al., 1998; Ogata et al., 1998; Ford et al., differences 1999). In addition, the expression of hIL-13R(cid:11)1 mRNAonhumanperipheralTcells wasshowntobe downregulated after stimulation by either anti-CD3 See Table 1. It is also of note that both human and plus anti-CD28 or anti-CD3 plus PMA (Gauchat mouse IL-13 receptors share approximately 25% et al., 1997). The activation of human monocytes by identity to the IL-5R(cid:11) chain. IL-13 results in the downregulation of IL-13R(cid:11)1 (Graber et al., 1998). Affinity for ligand(s) Release of soluble receptors See Table 2. In humans, soluble IL-13R(cid:11)1 has been detected in T cell supernatants (Graber et al., 1998). In mice, a soluble receptor is present in serum and urine which binds IL-13 with high affinity. Purification and sub- Table1 Percentageofsharedaminoacididentitybetween the IL-13-binding chains sequentpartialsequencingoftheproteinindicatethat it is the soluble form of mIL-13R(cid:11)2 protein (Zhang et al., 1997). huIL- huIL- mIL- mIL- 13R(cid:11)1 13R(cid:11)2 13R(cid:11)1 13R(cid:11)2 SIGNAL TRANSDUCTION huIL-13R(cid:11)1 100% 27% 74% 26% huIL-13R(cid:11)2 27% 100% 25% 59% Associated or intrinsic kinases mIL-13R(cid:11)1 74% 25% 100% 29% mIL-13R(cid:11)2 26% 59% 29% 100% Although the IL-13R(cid:11)1/IL-4R(cid:11) does not have an intrinsic kinase domain, it does associate with Table 2 Summary of the physical properties of the IL-13-binding chains: number of potential glycosylation sites and approximate affinities of IL-13 receptors for IL-13 Human Mouse IL-13R(cid:11)1 IL-13R(cid:11)2 IL-13R(cid:11)1 IL-13R(cid:11)2 sIL-13R(cid:11)2 M 70,000 70,000 60,000 70,000 40,000 r Mature peptide 401aa 354aa 398aa 362aa n.k. Precursor peptide 427aa 380aa 424aa 383aa n.k. Glycosylation sites 10 4 4 4 n.k. Affinity K 4nM 450pM 2–10nM 250pM 35pM d +IL-4R(cid:11) 30pM n.c. 75pM n.c. – n.c.,nochange;n.k.,notknown;sIL-13R(cid:11)2,solubleIL-13R(cid:11)2. 1516 David J. Matthews and Andrew N.J. McKenzie Table 3 Summary of cell types shown to express IL-13 receptor messenger RNA Tissue/cells hIL-13R(cid:11)1 mIL-13R(cid:11)1 hIL-13R(cid:11)2 mIL-13R(cid:11)2 Brain yes not detected yes yes Spleen yes yes yes yes Liver yes yes yes yes Fetal liver yes unknown yes unknown Thymus yes yes yes unknown Heart yes yes yes unknown Lung yes yes yes unknown Kidney yes yes unknown not detected Testis yes yes yes not detected Stomach yes yes yes unknown Skin yes yes yes unknown Appendix yes unknown yes unknown PBC yes unknown yes unknown Bone marrow yes no yes unknown Skeletal muscle yes no yes unknown Colon yes yes unknown unknown Small intestine yes unknown unknown unknown Ovary yes unknown unknown unknown Prostate yes unknown unknown unknown Pancreas yes unknown yes unknown B cells yes unknown yes unknown T cells yes unknown yes unknown Endothelial cells yes unknown yes unknown members of the JAK kinase family. The IL-13 be downregulated by SOCS proteins (Starr et al., receptor hasbeen shown to phosphorylate JAK2 and 1997). In addition, IL-13 also induces the phosphor- TYK2 in fibroblasts (Murata et al., 1998), JAK1, ylation of IRS-1/2 and IL-4R(cid:11) (Keegan et al., 1995) TYK2 in B9 cells (Welham et al., 1995), JAK1 in and activates PI-3 kinase (Wright et al., 1999). In TF-1 cells (Keegan et al., 1995), JAK1, JAK2 and human monocytes, IL-13 has been described as TYK2 in monocytes (Roy and Cathcart, 1998) and inducing cAMPproduction, PLC(cid:13)1 activation,phos- coloncarcinomacelllines(Murataetal.,1996).Partial phoinositol metabolism, and mobilization of intra- deletion analysis of the cytoplasmic domain of IL- cellular calcium stores (Sozzani et al., 1998). The 13R(cid:11)1 cells has noted that the terminal 38 amino tyrosine phosphatase SHP-1 has been implicated in acids were not necessary for proliferation or for the the negative regulation of IL-13 signal transduction tyrosine phosphorylation of JAK1 or TYK2 in FD5 (Haque et al., 1998). cells (Orchansky et al., 1999). There is no evidence that JAK3 kinase is involved in IL-13 signal transduction (Keegan et al., 1995). DOWNSTREAM GENE ACTIVATION Cytoplasmic signaling cascades Transcription factors activated The IL-13R initiates a JAK/STAT signaling cascade resultingintheactivationofSTAT6(Linetal.,1995) STAT6 is activated upon IL-13 receptor activation and STAT3 (Orchansky et al., 1999) and which may and is an important mediator of IL-13 function IL-13 Receptor 1517 (Linetal.,1995;Palmer-Crockeretal.,1996).STAT3 Human abnormalities has also been reported to be activated by IL-13 (Orchansky et al., 1999). The transcription factors There have not been cases described where either c-fos, c-jun, and c-myc have also been shown to be IL-13 receptor has been directly implicated in a upregulated by IL-13 (Doucet et al., 1998). human abnormality; however, in certain cases some polymorphismsintheIL-4R(cid:11)chainhavebeenshown Genes induced to be associated with atopy (Hershey et al., 1997; Mitsuyasu et al., 1998). The IL-13R has been found to be overexpressed and amarker for humangliomas Notable genes induced or upregulated by IL-13 (Debinski et al., 1999a,b). include CD23 (Punnonen et al., 1993), MHC class II, and in human B cells surface IgM (Zurawski and de Vries, 1994). VCAM-1 is found to be upregulated in THERAPEUTIC UTILITY fibroblasts (Doucet et al., 1998) and endothelial cells (Kotowicz et al., 1996). Effect of treatment with soluble receptor domain Promoter regions involved There are no published work describing the effects A STAT6 response element has been described in of using the soluble IL-13 receptor for therapeutic the IL-4 promoter GTCTGATTTCAGGAACAA- purposes in humans. In mice, treatment with a TTTTA (Curiel et al., 1997). recombinant soluble IL-13R(cid:11)2-Fc fusion protein impaired the expulsion of nematode worms (Urban BIOLOGICAL CONSEQUENCES et al., 1998). A soluble form of the mIL-13R(cid:11)1 has OF ACTIVATING OR INHIBITING also been administered to mice and found to increase the production of IgG2a and IgG2b in germinal RECEPTOR AND center B cells (Poudrier et al., 1999). PATHOPHYSIOLOGY Effects of inhibitors (antibodies) to Unique biological effects of receptors activating the receptors There is no published works describing the effects of In humans, only IL-4 and IL-13 have been reported using anti-IL-13 receptor antibodies for therapeutic to induce antibody class-switching to IgE (Punnonen purposes. However, the mutant form of human IL-4, et al., 1993), which is a major mediator of allergic Y124D,isapotentantagonistofbothIL-4andIL-13 responses. Therefore, IL-13 and its receptor are likely (Kruse et al., 1992; Aversa et al., 1993; Matthews to have an important role in the pathology of atopy. et al., 1997) and may have therapeutic potential. Inmice,IL-13hasbeendemonstratedtoplayaunique Some antibodies to the IL-4R(cid:11) chain have been role in inducing the rapid expulsion of certain shown to inhibit B cell responses to both IL-4 and nematode worms, suggesting an important role for IL-13 (Zurawski et al., 1995; Matthews et al., 1997). IL-13 in gut immunology (McKenzie et al., 1998b). Phenotypes of receptor knockouts References and receptor overexpression mice Aman, J., Tayebi, N., Obiri, N., Puri, R., Modi, W., and Leonard, W. (1996). cDNA cloning and characterisation of As yet, neither IL-13R molecules have been knocked the human interleukin 13 receptor (cid:11) chain. J. Biol. Chem. out. However, mice deficient in both the IL-4R(cid:11) 271,29265–29270. chain(Barneretal.,1998)andSTAT6(Takedaetal., Aversa, G., Punnonen, J., Cocks, B., de Waal Malefyt, R., 1996) have been generated and these mice have Vega, F. J., Zurawski, S., Zurawski, G., and de Vries, J. impaired TH2 cell development and fail to expel (1993). An interleukin-4 (IL-4) mutant protein inhibits both IL-4 and IL-13-induced human immunoglobulin G4 (IgG4) nematode infections efficiently (Urban et al., 1998). and IgE synthesis and B cell proliferation: support for a com- These results are in concordance with findings for mon component shared by IL-4 and IL-13 receptors. J. Exp. IL-13-deficient mice (McKenzie et al., 1998b). Med.178,2213–2218. 1518 David J. Matthews and Andrew N.J. McKenzie Barner, M., Mohrs, M., Brombacher, F., and Kopf, M. (1998). Hilton,D.,Zhang,J.-G.,Metcalf,D.,Alexander,W.,Nicola,N., Differences between IL-4R(cid:11)-deficient and IL-4-deficient mice andWilson,T.(1996).Cloningandcharacterisationofabind- reveal a role for IL-13 in the regulation of Th2 responses. ingsubunitoftheinterleukin13receptorthatisalsoacompo- Curr.Biol.8,669–672. nentoftheinterleukin4receptor.Proc.NatlAcad.Sci.USA93, Callard,R.E.,Matthews,D.J.,andHibbert,L.(1996).IL-4and 497–501. IL-13receptors:aretheyoneandthesame?Immunol.Today17, Keegan, A., Johnston, J., Tortolani, P., McReynolds, L., 108–110. Kinzer, C., O’Shea, J., and Paul, W. (1995). Similarities and Caput, D., Laurent, P., Kaghad, M., Lelias, J.-M., Lefort, S., differences in signal transduction by interleukin 4 and inter- Vita, N., and Ferrara, P. (1996). Cloning and characterisation leukin 13: analysis of janus kinase activation. Proc. Natl of a specific interleukin (IL)-13 binding protein structurally Acad.Sci.USA92,7681–7685. related to the IL-5 receptor (cid:11) chain. J. Biol. Chem. 271, Kotowicz, N., Callard, R., Friedrich, K., Matthews, D., and 16921–16926. Klein, N. (1996). Biological activity of IL-4 and IL-13 on Curiel,R.,Lahesmaa,R.,Subleski,J.,Cippitelli,M.,Kirken,R., humanendothelialcells:functionalevidencethatbothcytokines Young, H., and Ghosh, P. (1997). Identification of a Stat6- actthroughthesamereceptor.Int.Immunol.8,1915–1925. responsive element in the promoter of the human interleu- Kruse,N.,Tony,H.,andSebald,W.(1992).Conversionofhuman kin-4gene.Eur.J.Immunol.27,1982–1987. interleukin-4 into a high affinity antagonist by a single amino Debinski, W., Gibo, D. M., Hulet, S. W., Connor, J. R., and acidreplacement.EMBOJ.11,3237–3244. Gillespie,G.Y.(1999a).Receptorforinterleukin13isamarker Kuznetsov,V.A.,andPuri,R.K.(1999).Kineticanalysisofhigh and therapeutic target for human high-grade gliomas. Clin. affinity forms of interleukin (IL)-13 receptors: suppression of CancerRes.5,985–990. IL-13 binding by IL-2 receptor gamma chain. Biophys. J. 77, Debinski, W., Gibo, D. M., Slagle, B., Powers, S. K., and 154–172. Gillespie, G. Y. (1999b). Receptor for interleukin 13 is abun- Lin, J.-X., Migone, T.-S., Tsang, M., Friedmann, M., dantlyandspecificallyover-expressedinpatientswithglioblas- Weatherbee,J.,Zhou,L.,Yamauchi,A.,Bloom,E.,Meitz,J., tomamultiforme.Int.J.Oncol.15,481–486. John,S.,andLeonard,W.(1995).Theroleofsharedreceptor Donaldson, D. D., Whitters, M. J., Fitz, L. J., Neben, T. Y., motifsandcommonStatproteinsinthegenerationofcytokine Finnerty,H.,Henderson,S.L.,O’Hara,R.M.J.,Beier,D.R., pleiotropyandredundancybyIL-2,IL-4,IL-7,IL-13andIL-5. Turner,K.J.,Wood,C.R.,andCollins,M.(1998).Themurine Immunity2,331–339. IL-13receptoralpha2:molecularcloning,characterization,and Manna,S.K.,andAggarwal,B.B.(1998).IL-13suppressesTNF- comparison with murine IL-13 receptor alpha 1. J. Immunol. induced activation of nuclear factor-(cid:20)B, activation protein-1, 161,2317–2324. andapoptosis.J.Immunol.161,2863–2872. Doucet,C.,Brounty-Boye,D.,Pottin-Clemenceau,C.,Jasmin,C., Matthews, D.,Clark, P., Herbert, J., Morgan, G., Armitage, R., Canonica, G. W., and Azzarone, B. (1998). IL-4 and IL-13 Kinnon, C., Minty, A., Grabstein, K., Caput, D., Ferrara, P., specificallyincreaseadhesionmoleculeandinflammatorycyto- and Callard, R. (1995). Function of the interleukin-2 (IL-2) kine expression in human lung fibroblasts. Int. Immunol. 10, receptorgamma-chaininbiologicresponsesofX-linkedsevere 1421–1433. combined immunodeficient B cells to IL-2, IL-4, IL-13 and Ford, D., Sheehan, C., Girasole, C., Priester, R., Kouttab, N., IL-15.Blood85,38–42. Tigges, J., King, T. C., Luciani, A., Morgan, J. W., and Matthews, D. J., Hibbert, L., Friedrich, K., Minty, A., and Maizel, A. L. (1999). The human B cell response to IL-13 is Callard, R. E. (1997). X-SCID B cell responses to interleukin- dependentoncellularphenotypeaswellasmodeofactivation. 4 and interleukin-13 are mediated by a receptor complex that J.Immunol.163,3185–3193. includes the interleukin-4 receptor alpha chain (p140) but not Gauchat, J.-F., Schlagenhauf, E., Feng, N.-P., Moser, R., thegammacchain.Eur.J.Immunol.27,116–121. Yamage, M., Jeanin, P., Alouani, S., Elson, G., McKenzie, G., Bancroft, A., Grencis, R., and Mckenzie, A. Notarangelo,D.,Wells,T.,Eugster,H.-P.,andBonnefoy,J.-Y. (1998a).Adistinct roleforinterleukin-13 in Th2-cell-mediated (1997).Anovel4kbinterleukin-13receptor(cid:11)mRNAexpressed immuneresponses.Curr.Biol.8,339–342. inhumanB,T,andendothelialcellsencodinganalternatetype- McKenzie, G. J., Emson, C. L., Bell, S. E., Anderson, S., II interleukin-4/interleukin-13 receptor. Eur. J. Immunol. 27, Fallon,P.,Zurawski,G.,Murray,R.,andMcKenzie,A.N.J. 971–978. (1998b). Impaired development of Th2 cells in IL-13-deficient Graber, P., Gretener, D., Herren, S., Aubry, J. P., Elson, G., mice.Immunity9,423–432. Poudrier,J.,Lecoanet-Henchoz,S.,Alouani,S.,Losberger,C., Miloux, B., Laurent, P., Bonnin, O., Lupker, J., Caput, D., Bonnefoy, J. Y., Kosco-Vilbois, M. H., and Gauchat, J. F. Vita, N., and Ferrara, P. (1996). Cloning of the human (1998). The distribution of IL-13 receptor (cid:11)1 expression on IL-13R(cid:11)1chainandreconstitutionwiththeIL-4R(cid:11)ofafunc- Bcells,Tcells andmonocytesanditsregulation byIL-13and tionalIL-4/IL-13receptorcomplex.FEBSLett.401,163–166. IL-4.Eur.J.Immunol.28,4286–4298. Mitsuyasu,H.,Izuhara,K.,Mao,X.O.,Gao,P.S.,Arinobu,Y., Guo, J., Apiou, F., Mellerin, M. P., Lebeau, B., Jaques, Y., Enomoto, T., Kawai, M., Saski, S., Dake, Y., Hamasaki, N., and Minvielle, S. (1997). Chromosome mapping and expres- Shirakawa, T., and Hopkin, J. M. (1998). IleVal variant of sion of the human interleukin-13 receptor. Genomics 42, IL4RalphaupregulatesIgEsynthesisandassociateswithatopic 141–145. asthma.Nat.Genet.2,119–120. Haque,S.J.,Harbor,P.,Tabrizi,M.,Yi,T.,andWilliams,B.R. Murata,T.,Noguchi,P.,andPuri,R.(1996).IL-13inducesphos- (1998). Protein-tyrosine phosphatase Shp-1 is a negative regu- phorylation and activation of JAK2 janus kinase in human latorofIL-4-andIL-13-dependentsignaltransduction.J.Biol. colon carcinomacelllines: similarities between IL-4and IL-13 Chem.273,33893–33896. signalling.J.Immunol.156,2972–2978. Hershey,G.K.,Friedrich,M.F.,Esswein,L.A.,Thomas,M.L., Murata,T.,Husain,S.R.,Mohri,H.,andPuri,R.K.(1998).Two andChatila,T.A.(1997).Theassociationofatopywithagain- differentIL-13receptorchainsareexpressedinnormalhuman of-function mutation in the alpha subunit of the interleukin-4 skinfibroblasts,andIL-13mediatesignaltransductionthrough receptor.N.Engl.J.Med.337,1720–1725. acommonpathway.Int.Immunol.8,1103–1110. IL-13 Receptor 1519 Ogata,H.,Ford,D.,Kouttab,N.,King,T.C.,Vita,N.,Minty,A., Starr, R., Willson, T., Viney, E., Murray, L., Rayner, J., Stoeckler, J., Morgan, D., Girasole, C., Morgan, W. J., and Jenkins, B., Gonda, T., Alexander, W., Metcalf, D., Maizel,A.L.(1998).Regulationofinterleukin-13receptorcon- Nicola,N.,andHilton,D.(1997).Afamilyofcytokine-induci- stituentsonmaturehumanBlymphocytes.J.Biol.Chem.279, bleinhibitorsofsignalling.Nature387,917–921. 9864–9871. Takeda, K., Kamanaka, M., Tanaka, T., Kishimoto, T., and Orchansky,P.,Ayres,S.,Hilton,D.,andSchraeder,J.(1997).An Akira,S.(1996).ImpairedIL-13-mediatedfunctionsofmacro- interleukin (IL)-13 receptor lacking the cytoplasmic domain phagesinSTAT6-deficientmice.J.Immunol.157,3220–3222. fails to transduce IL-13-induced signals and inhibits responses Urban, J., Noben-Trauth, N., Donaldson, D., Madden, K., toIL-4.J.Biol.Chem.272,22940–22947. Morris, S., Collins, M., and Finkelman, F. (1998). IL-13, Orchansky,P.L.,Kwan,R.,Lee,F.,andSchrader,J.W.(1999). IL-4R and Stat6 are required for the expulsion of the gastro- Characterization of the cytoplasmic domain of interleukin-13 intestinal nematode parasite Nippostrongylus brasiliensis. receptor-alpha.J.Biol.Chem.274,20818–20825. Immunity8,255–264. Palmer-Crocker, R., Hughes, C., and Pober, J. (1996). IL-4 and Welham, M. J., Learmonth, L., Bone, H., and Schrader, J. W. IL-13 activate the JAK2 tyrosine kinase and Stat6 in cultured (1995).Interleukin-13signaltransductioninlymphohemopoie- human vascular endothelial cells through a common pathway ticcells.Similaritiesanddifferencesinsignaltransductionwith thatdoesnotinvolvethe(cid:13)cchain.J.Clin.Invest.98,604–609. interleukin-4andinsulin.J.Biol.Chem.270,12286–12296. Poudrier, J., Graber, P., Herren, S., Gretener, D., Elson, G., Wright, K., Kolios, G., Westwick, J., and Ward, S. G. (1999). Berney, C., Gauchat, J. F., and Kosco-Vilbois, M. H. (1999). Cytokine-inducedapoptosisinepithelialHT-29cellsisindepen- A soluble form of IL-13 receptor alpha 1 promotes IgG2a dent ofnitric oxide formation. Evidence foran interleukin-13- and IgG2b production by murine germinal center B cells. driven phosphatidylinositol 3-kinase-dependent survival J.Immunol.163,1153–1161. mechanism.J.Biol.Chem.274,17193–17201. Punnonen, J., Aversa, G., Cocks, B., Mckenzie, A., Menon, S., Zhang, J., Hilton, D., Willson, T., McFarlane, C., Roberts, B., Zurawski, G., de Waal Malefyt, R., and de Vries, J. (1993). Moritz, R., Simpson, R., Alexander, W., Metcalf, D., and Interleukin-13 induces interleukin-4-independent IgG4 and Nicola,N.(1997).Identification,purificationandcharacterisa- IgE synthesis and CD23 expression by human B-cells. Proc. tion of a soluble interleukin (IL)-13-binding protein. Evidence NatlAcad.Sci.USA90,3730–3734. thatitisdistinctfromtheclonedIL-13receptorandIL-4recep- Roy,B.,andCathcart,M.K.(1998).Inductionof15-lipoxygenase toralphachains.J.Biol.Chem.272,9474–9480. expression by IL-13 requires tyrosine phosphorylation of Zurawski,G.,anddeVries,J.(1994).Interleukin13,aninterleu- JAK2 and TYK2 in human monocytes. J. Biol. Chem. 273, kin4-likecytokinethatactsonmonocytesandB-cellsbutnot 32023–32029. onT-cells.Immunol.Today15,19–26. Sozzani, P., Hasan, L., Seguelas, M. H., Caput, D., Ferrara, P., Zurawski, S., Chomarat, P., Djossou, O., Bidaud, C., Pipy, B., and Cambon, C. (1998). Il-13 induces tyrosine phos- Mckenzie, A., Miossec, P., Banchereau, J., and Zurawski, G. phorylation of phospholipase C gamma-1 following IRS-2 (1995).Theprimarybindingsubunitofthehumaninterleukin-4 association in human monocytes: relationship with the inhibi- receptor is also a component of the interleukin-13 receptor. toryeffectofIL-13onROIproduction.Biochem.Biophy.Res. J.Biol.Chem.270,13869–13878. Commun.244,665–670.

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