IL-13 Receptor

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 There are two membrane-bound IL-13-binding proteins, IL-13R1 and IL-13R2. The IL-13R1 protein has a moderate affinity for IL-13 but requires the presence of IL-4R (CD124) to form a high-affinity receptor complex. IL-4R alone does not bind IL-13. Signaling through the IL-13R1/IL-4R complex activates STAT6 and IRS-1/2, and IL-13R1 appears to recruit a JAK kinase to the activated receptor. In contrast, IL-13R2 alone is a high-affinity receptor for IL-13 but there is little evidence that this protein has signal transduction properties. The function of IL-13R2 is still unclear, however, it has been proposed that it may act as an IL-13 antagonist. Both receptor chains have a wide tissue distribution, although notably, the IL-13R1 receptor does not appear to be expressed on the surface of T cells.

BACKGROUND

Discovery Two IL-13-binding chains have been identified following the cloning of IL-13. Using an expression cloning approach, Caput et al. (1996) identified IL13R2, a membrane-bound human protein with a high affinity for IL-13 but no apparent capacity for signal transduction. In contrast, Hilton et al. (1996) obtained a second type of IL-13 receptor by screening a mouse genomic library using redundant oligonucleotides to the WSXWS motif (a conserved motif found in all class I cytokine receptors). This approach identified IL-13R1, a low-affinity IL-13 binding chain, that requires the presence of the IL-4R chain (CD124) in order to form a high-affinity IL-13 receptor. As a consequence, the IL-4R/IL-13R1 complex was also identified as a functional IL-4

receptor (the type II IL-4 receptor) (Callard et al., 1996). The relationship between the IL-13R1 and IL-13R2 is not clear but there is evidence that IL13R2 may act as an IL-13 antagonist. The c chain, the promiscuous receptor chain found in the IL-2, IL-4, IL-7, IL-9, and IL-15 receptors, does not appear to be a functional component of the IL-13 receptor (Matthews et al., 1995).

Alternative names A number of groups have cloned both IL-13 receptors in humans (Aman et al., 1996; Caput et al., 1996; Miloux et al., 1996; Gauchat et al., 1997) and in mice. The IL-13R1 has also been termed 0 and the IL-13R2 has also been called IL-13R0 .

Structure Both IL-13R1 and IL-13R2 are members of the class I cytokine receptor family and have a similar structure to the IL-5R chain and contain a WSXWS motif. The main structural difference between the two IL-13 receptors is that the IL-13R1 chain has a longer intracellular domain than IL-13R2.

Main activities and pathophysiological roles Signals generated by the IL-13R1/IL-4R receptor complex promote TH2-driven immunological responses important in parasitic worm infections and atopy (McKenzie et al., 1998a, 1998b). In humans, the signals generated by the IL-13 receptor promote the production of IgE (Punnonen et al., 1993) but inhibit the production of TH1 proinflammatory mediators such as TNF (Manna and Aggarwal, 1998).

1512 David J. Matthews and Andrew N.J. McKenzie

GENE

Human IL-13R2: X95302 Mouse IL-13R2: U65747

Accession numbers

Sequence

Human IL-13R1: Y09328 Mouse IL-13R1: S80963

See Figure 1.

Figure 1 Nucleotide sequences for human and mouse IL-13R1 and IL-13R2. hIL-13Rα1 1 CGGGTAATTT 61 CCGGGCTCCG 121 CTGCTGCTCT 181 CCACCTGTGA 241 AATCCACCCG 301 AAACAAGATA 361 AGGATTTGTC 421 TTGGTTGAAA 481 CAATGCATTT 541 AGTCCCGACA 601 TGTGAAAACA 661 AAGGATTCCA 721 ATTAAACCAT 781 ATTAAAAACC 841 TTTATTAGCA 901 AATGTTTTCT 961 AATACATCTT 1021 AGAGTCAAAA 1081 GAAATGAGTA 1141 CCAGTCATCG 1201 ATTATATTCC 1261 AATGATGATA 1321 ACCGACTCTG 1381 ATTTTTACCT 1441 ACTTATTAGA 1501 ACAGGTCTTT 1561 TACTATGAGT

TTTCAAAGTA AGGCGAGAGG GCGCCGGCGG CAAATTTGAG AGGGAGCCAG AGAAAATAGC TGCAAGTGGG AATGCATCTC GGCACAACCT CTAACTATAC TCTTTAGAGA GTTTTGAACA CCTTCAATAT TCTCCTTCCA GATGCCTATT ACGTCCAAGA GTTTCATGGT CAAATAAGTT TAGGTAAGAA TCGCAGATGC CTCCAATTCC CTCTGCACTG TAGTGCTGAT TCACTGTGAC TGGAAACTGA ATGTTGAGTC GG

AACGCTTCGG CTGCATGGAG CGGGGGCGGG TGTCTCTGTT CTCAAATTGT TCCGGAAACT GTCCCAGTGT ACCCCCAGAA GAGCTACATG TCTCTACTAT AGGCCAATAC ACACAGTGTC AGTGCCTTTA CAATGATGAC TTATGAAGTA GGCTAAATGT CCCTGGTGTT ATGCTATGAG GCGCAATTCC AATCATAGTA TGATCCTGGC GAAGAAGTAC AGAAAACCTG CTTGAGAAGA AACTACTGCA GCTAGCAAGA

GCCCCGCGGG TGGCCGGCGC GGCGGGGGCG GAAAACCTCT AGTCTATGGT CGTCGTTCAA AGCACCAATG GGTGATCCTG AAGTGTTCTT TGGCACAGAA TTTGGTTGTT CAAATAATGG ACTTCCCGTG CTATATGTGC GAAGTCAATA GAGAATCCAG CTTCCTGATA GATGACAAAC ACACTCTACA CTCCTGCTTT AAGATTTTTA GACATCTATG AAGAAAGCCT TTCTTCCCAT CCATTTAAAA ACAAGAAAAG

ACACTCAGCT GGCTCTGCGG CCGCGCCTAC GCACAGTAAT ATTTTAGTCA TAGAAGTACC AGAGTGAGAA AGTCTGCTGT GGCTCCCTGG GCCTGGAAAA CCTTTGATCT TCAAGGATAA TGAAACCTGA AATGGGAGAA ACAGCCAAAC AATTTGAGAG CTTTGAACAC TCTGGAGTAA TAACCATGTT ACCTAAAAAG AAGAAATGTT AGAAGCAAAC CTCAGTGATG TCTCCATTTG ACAGGCAGCT TTTTAAAGAA

AAGAGCCCGG GCTGTGGGCG GGAAACTCAG ATGGACATGG TTTTGGCGAC CCTGAATGAG GCCTAGCATT GATTGAGCTT AAGGAATACC AATTCATCAA GACCAAAGTG TGCAGGAAAA TCCTCCACAT TCCACAGAAT TGAGACACAT AAATGTGGAG AGTCAGAATA TTGGAGCCAA ACTCATTGTT GCTCAAGATT TGGAGACCAG CAAGGAGGAA GAGATAATTT TTATCTGGGA CATAAGAGCC AGATGTTGCT

hIL-13Rα2 1 GTAAGAACAC 61 ACCTGGTCAG 121 GAGAAATGGC 181 CATTTGGCTG 241 AGATAGTGGA 301 TGGATCATTT 361 AAACATGGAA 421 AGGGCATTGA 481 TTCAAAGTTC 541 AAGTTCAGGA 601 CTGGCATAGG 661 ATCATGCATT 721 TTCCCTATTT 781 AGAACAAGCC 841 TGCCGCCAGT 901 GCATACCTTT 961 ATGATACTAC 1021 ATGAAACCCG 1081 ACGGAATTTG 1141 AAACTTTGCT 1201 CCGGTCTGCT 1261 ATACATGAAG 1321 CCAAATGTTC

TCTCGTGAGT AAGTGTGCCT TTTCGTTTGC TACTTCATCT TCCCGGATAC TAAGGAATGC GACCATCATT AGCGAAGATA CTGGGCAGAA TATGGATTGC TGTACTTCTT ACAGTGTGTT GGAGGCATCA TATCAGATCC CTATCTTACT GGGACCTATT CTTGGTGACT ACAATTATGC GAGTGAGTGG ACGTTTCTGG TTTGCGTAAG ACTTTCCATA AATATGAGTC

CTAACGGTCT GTCGGCGGGG TTGGCTATCG TCAGACACCG TTAGGTTATC ACAGTGGAAT ACTAAGAATC CACACGCTTT ACTACTTATT GTATATTACA GATACCAATT GATTACATCA GACTATAAAG AGTTATTTCA TTTACTCGGG CCAGCAAGGT GCTACAGTTG TTTGTAGTAA AGTGATAAAC CTACCATTTG CCAAACACCT TCAAGAGACA TCAATAAACT

TCCGGATGAA AGAGAGGCAA GATGCTTATA AGATAAAAGT TCTATTTGCA ATGAACTAAA TACATTACAA TACCATGGCA GGATATCACC ATTGGCAATA ACAACTTGTT AGGCTGATGG ATTTCTATAT CTTTTCAGCT AGAGTTCATG GTTTTGATTA AAAATGAAAC GAAGCAAAGT AATGCTGGGA GTTTCATCTT ACCCAAAAAT TGGTATTGAC GAATTTTTCT

GGCTATTTGA TATCAAGGTT TACCTTTCTG TAACCCTCCT ATGGCAACCC ATACCGAAAC AGATGGGTTT ATGCACAAAT ACAAGGAATT TTTACTCTGT TTACTGGTAT ACAAAATATA TTGTGTTAAT TCAAAATATA TGAAATTAAG TGAAATTGAG ATACACCTTG GAATATTTAT AGGTGAAGAC AATATTAGTT GATTCCAGAA TCAACAGTTT TGCGAATGTT

AGTCGCCATA TTAAATCTCG ATAAGCACAA CAGGATTTTG CCACTGTCTC ATTGGTAGTG GATCTTAACA GGATCAGAAG CCAGAAACTA TCTTGGAAAC GAGGGCTTGG GGATGCAGAT GGATCATCAG GTTAAACCTT CTGAAATGGA ATCAGAGAAG AAAACAACAA TGCTCAGATG CTATCGAAGA ATATTTGTAA TTTTTCTGTG CCAGTCATGG GAAAAA

IL-13 Receptor 1513 Figure 1(b) (Contd. ) mIL-13Rα1 1 TGAAAAGATA 61 ATGGCGCGGC 121 GGCCAAGTTG 181 GAAAATCTCT 241 ACTCTCAGAT 301 CATCGTAAAG 361 AGTGCCAATG 421 GGTGATCCTG 481 AAGTGTTCCT 541 TGGTACAGCA 601 ATTGCTTGTT 661 ATAATGGTCA 721 TCCTATGTGA 781 TTAGTGCAGT 841 GTCAATAATA 901 AATTCCGAAT 961 GCCGACGCTG 1021 AACAAACTGT 1081 TTCTACACCA 1141 CTTTTTTACC 1201 ATTTTTAAAG 1261 ATCTATGAGA 1321 AAAGCAGCTC 1381 GATTTATTGC 1441 CTTGAAAAAC 1501 CCAAACCCAA 1561 CCCTAAAAGC 1621 ACCATCAATT mIL-13Rα2 1 GGCACGAGGG 61 CTGAACAGTG 121 TAGAGATTCA 181 CTGTGATAAT 241 CCTGGAGAAA 301 ACTGGCTATT 361 GGATTACTTG 421 GGCTGTACAC 481 ATAATTACTA 541 AAGATACGTA 601 ATAGAAGCTT 661 AAGTGTATAT 721 TATTCTGATA 781 TGTGCTGATT 841 TCATCAGACT 901 AGATCCAGCT 961 CTTCATATTA 1021 CCCATTCCAC 1081 GAGTCTGCCA 1141 CTATGCTTTT 1201 GAATGGAGTG 1261 ATAGTACCAG 1321 AAGGAAGAAC 1381 TATGAAGATA 1441 ATATTAAACT 1501 CTAATAGTGT 1561 AAAAAAA

GAATAAATGG CAGCGCTGCT CCGCGGCCAC GCACGATAAT ATTTTAGTCA AGGAATTACC AAAGTGAGAA AGTCCGCTGT GGCTCCCTGG GCCTGGAGAA CCTTTAAATT AGGATAATGC AACCTGATCC GGAAGAATCC CTCAAACCGA CTGATAGAAA TCTACACAGT GGAGTGATTG CCATGTTACT TGAAAAGGCT AAATGTTTGG AACAATCCAA CTTGATGGGG ATTCTCCATT AGGCAGCTCC AGGAGCTCCT AGATGTTTTG CATCTAATCA

CCTCGTGCCG GGGCGAGCTG AGAAGTTCAG ATGGACGTGG CTTTGATGAC CCTGGATGAG GCCTAGCCCT GACTGAGCTC AAGGAATACA AAGTCGTCAA GACTAAAGTG TGGGAAAATT TCCACATATT ACAAAATTTT CCGACATAAT CATGGAGGGT CAGAGTAAGA GAGTGAAGCA CACCATTCCA TAAGATCATT AGACCAGAAT AGAAGAAACG AGAAGTGATT TGTTATCTGG TAAGAGCCAC TCCAAGAAAA CCAAATCCCC GGAATTGTGA

AATTCGGCAC TTGGTGCTGC CCACCTGTGA AGTCCTCCTG CAACAGGATA AAAATCTGTC TTGGTGAAAA AAGTGCATTT AGCCCTGACA TGTGAAAACA GAACCTAGTT AGGCCATCCT AAACATCTTC AGAAGCAGAT ATTTTAGAGG ACAAGTTGTT GTCAAAACAA CAGAGTATAG GTCTTTGTCG ATATTTCCTC GATGATACCC GATTCTGTAG TCTTTCTTGC GGGACTTGTT AGGTCTTGAT GCAAGAGTTC AAACTAGAGG TGGCTTCCTA

GAGCCGAGGC TACTGTGGAC CGAATTTGAG AAGGAGCCAG AGAAAATTGC TGCAGGTGGG AGTGCATCTC GGCATAACCT CACACTATAC TCTATAGAGA TTGAACATCA GCAAAATAGT TCCTCAAAAA GCTTAACTTA TTGAAGAGGA TCCAACTCCC ACAAGTTATG GTAAGGAGCA CAGTGGCAGT CAATTCCTGA TGCACTGGAA TGCTGATAGA CTTCAATGTG AAATAGAAAC GTGACTTTTG TTCTCGTTCC ACAAAGACAA AGGAATCTCT

GAGGGCCTGC CGCCACCGTG CGTCTCTGTC TCCAAATTGC TCCAGAAACT CTCTCAGTGT ACCCCCTGAA GAGCTATATG TCTGTACTAT AGGTCAACAC GAACGTTCAA GTCTTTAACT TGGTGCCTTA TGAAGTGGAG CAAATGCCAG TGGTGTTCTT CTTTGATGAC AAACTCCACC CATAATCCTC TCCTGGCAAG GAAGTATGAC AAACCTGAAG ACCCTGTGAA TGAAACTACT CATTGAAAAC TTGTTCCAAT GGGGACAATG GCTTGCTCTG

AGAGGAGGAG ACCTCTCTCA ATTTAGTGTC ACATTTCTTG TGGCTTTTGT CTTTGGAGAT GTTATCTCTA TAGAATATGA GGAATCTAAT CGCATTTGTC CTTATGGGAT ATTATAACTG CCAACTATAC ACCTCCAGCA ATAAAGATTT ATACAGTTTT GTGTGGAGAA CAAGGTGTTA CAGACAAAAA TTGTAAGATG AAGAGGAATG TTTGTCTTTT CTGAACCCAC CCCTCTGTTA CAATTTCTCT TGGGTTTTTG

GGAAAGATAG AGACAGTGCT TAATGTGGAA AGAAACCATA GCATATCAGA AAAAGTTAAT TTTGCAATGG GTTAAAATAC TTACAAGGAT AGAGCATTGT ATCAGATGAA GCAGTATTTG CATGTTTTTC TGATGAAAAA TTTTATCTGT TCAACTTCAA TTCCATTGAT CACTTATGAA CGATATGAAG TAAGGTCAAT TTGGGAAGGT CTTTATATTC ATTGAGCCTC AACCACCAAT TAAAATTTCG ACTAAAGTGC

AAAGAGAGAG TTGCTCTTCA AGGAGGACAA TTATTGAGTA TGCTTGTGTT CCTCCTCAGG AAACCTCCTG CGAAATGTTG GGGTTTGATC ACAAATGGAT GGAAGTTTGG GTCTGCTCTT TGGTATGAGG AATGTTGGAT GTTAATGGAT AATATAGTTA ATTAGAATGA ATTGTGATCC TTGAAGAGGA ATATATTGTG TACACAGGGC CTTTTGTTAC CATGTGGATC TTCTTGACAT AATACATCTT TGGATATATA

AGAAAGATTG CGTATAAGGA AGAGGTCTTG GAGCTTTCAG TCATTCTTCT ATTTTGAAAT TGGTTATAGA ATAGCGACAG TTAATAAAGG CAGAAGTACA AAACTAAAAT GGAAACCTGG GCTTGGATCA GCAAACTGTC CTTCAAAGTT AACCATTGCC AATGGAGCAC GAGAAGACGA GAGCAAATGA CAGATGATGG CAGACTCAAA TTCTTTGCCT TGAACAAAGA AGAGCCAGCC CTTGAAAATC TCTCCAAAAA

CTTGCTACCC AGGAAAACAG TGATAACTGC CACACTAAAT TTGTACAATA ATTGGATCCT AAAATTTAAG CTGGAAGACT CATTGAAGGA AAGTCCATGG TCAGGACATG CAAGACAGTA TGCCTTACAG CAACTTGGAC GGAACCCATC ACCAGAATTC ACCTGGAGGA TATTTCCTGG AAGTGAAGAC AATTTGGAGC GATTATTTTC TATTGTGGAG AGTGTGTGCT AGCAGGAGTC AGTGTTTGTC AAAAAAAAAA

Chromosome location and linkages The location of the huIL-13R1 gene is at present unknown. The huIL-13R2 gene is located on the X

chromosome in the region Xq24 (Guo et al., 1997). Both murine genes map to the X chromosome (Donaldson et al., 1998). Murine IL-13R1 maps to the region DXMit85: 3.8  2.1 cM (mIL-13R1,

1514 David J. Matthews and Andrew N.J. McKenzie Agtr2) 3.8  2.1 cM: DXMit49. Murine IL-13R2 maps to the region DXMit4: 6.4  2.5 cM (mIL13R2, DXMit34) 7.9  2.9 cM: DXMit120.

PROTEIN

Accession numbers Human IL-13R1: P78552 Mouse IL-13R1: O09030 Human IL-13R2: Q14627 Mouse IL-13R2: 3483094

Sequence See Figure 2.

Description of protein Both IL-13R1 and IL-13R2 proteins contain an Nterminal immunoglobulin-like domain followed by a class I cytokine receptor region including a WSXWS motif near the transmembrane domain. The human and mouse IL-13R1 proteins have a cytoplasmic region capable of signal transduction and contain Box 1 and Box 2 motifs. Although the IL-4R chain has no measurable ability to bind IL-13 (Zurawski et al., 1995), it does, however, act as an affinity converter for IL-13R1, increasing its affinity for IL-13 by 100fold (Hilton et al., 1996). The role of IL-13R2 is unclear, although it has a very short intracellular domain and it does not appear to be involved in signal transduction. The IL-13 receptor displays a high degree of complexity in its relationship with its ligands and with the IL-4 receptor (Callard et al., 1996). IL-13

Figure 2 Amino acid sequences for human and mouse IL-13R1 and IL-13R2. Putative signal peptides are shown in bold. huIL-13Rα1 1 MEWPARLCGL 61 NCSLWYFSHF 121 PEGDPESAVT 181 QYFGCSFDLT 241 DDLYVQWENP 301 GVLPDTLNTV 361 IVLLLYLKRL 421 NLKKASQ huIL-13Rα2 1 MAFVCLAIGC 61 HFKECTVEYE 121 SSWAETTYWI 181 ALQCVDYIKA 241 PVYLTFTRES 301 TRQLCFVVRS 361 LLLRKPNTYP mIL-13Rα1 1 MARPALLGEL 61 TLRYFSHFDD 121 GDPESAVTEL 181 IACSFKLTKV 241 LVQWKNPQNF 301 ADAVYTVRVR 361 LFYLKRLKII 421 KAAP mIL-13Rα2 1 MAFVHIRCLC 61 LEYELKYRNV 121 SYGISDEGSL 181 YLQHDEKNVG 241 SVENSIDIRM 301 FVRCKVNIYC 361 PEPTLSLHVD

WALLLCAGGG GDKQDKKIAP ELQCIWHNLS KVKDSSFEQH QNFISRCLFY RIRVKTNKLC KIIIFPPIPD

GGGGGAAPTE ETRRSIEVPL YMKCSWLPGR SVQIMVKDNA EVEVNNSQTE YEDDKLWSNW PGKIFKEMFG

TQPPVTNLSV NERICLQVGS NTSPDTNYTL GKIKPSFNIV THNVFYVQEA SQEMSIGKKR DQNDDTLHWK

SVENLCTVIW QCSTNESEKP YYWHRSLEKI PLTSRVKPDP KCENPEFERN NSTLYITMLL KYDIYEKQTK

TWNPPEGASS SILVEKCISP HQCENIFREG PHIKNLSFHN VENTSCFMVP IVPVIVAGAI EETDSVVLIE

LYTFLISTTF LKYRNIGSET SPQGIPETKV DGQNIGCRFP SCEIKLKWSI KVNIYCSDDG KMIPEFFCDT

GCTSSSDTEI WKTIITKNLH QDMDCVYYNW YLEASDYKDF PLGPIPARCF IWSEWSDKQC

KVNPPQDFEI YKDGFDLNKG QYLLCSWKPG YICVNGSSEN DYEIEIREDD WEGEDLSKKT

VDPGYLGYLY IEAKIHTLLP IGVLLDTNYN KPIRSSYFTF TTLVTATVEN LLRFWLPFGF

LQWQPPLSLD WQCTNGSEVQ LFYWYEGLDH QLQNIVKPLP ETYTLKTTNE ILILVIFVTG

LVLLLWTATV QQDKKIAPET KCIWHNLSYM EPSFEHQNVQ RSRCLTYEVE VKTNKLCFDD IFPPIPDPGK

GQVAAATEVQ HRKEELPLDE KCSWLPGRNT IMVKDNAGKI VNNTQTDRHN NKLWSDWSEA IFKEMFGDQN

PPVTNLSVSV KICLQVGSQC SPDTHYTLYY RPSCKIVSLT ILEVEEDKCQ QSIGKEQNST DDTLHWKKYD

ENLCTIIWTW SANESEKPSP WYSSLEKSRQ SYVKPDPPHI NSESDRNMEG FYTTMLLTIP IYEKQSKEET

SPPEGASPNC LVKKCISPPE CENIYREGQH KHLLLKNGAL TSCFQLPGVL VFVAVAVIIL DSVVLIENLK

FILLCTITGY DSDSWKTIIT ETKIQDMKCI CKLSNLDSSD KWSTPGGPIP ADDGIWSEWS LNKEVCAYED

SLEIKVNPPQ RNLIYKDGFD YYNWQYLVCS YKDFFICVNG PRCYTYEIVI EEECWEGYTG TLC

DFEILDPGLL LNKGIEGKIR WKPGKTVYSD SSKLEPIRSS REDDISWESA PDSKIIFIVP

GYLYLQWKPP THLSEHCTNG TNYTMFFWYE YTVFQLQNIV TDKNDMKLKR VCLFFIFLLL

VVIEKFKGCT SEVQSPWIEA GLDHALQCAD KPLPPEFLHI RANESEDLCF LLCLIVEKEE

IL-13 Receptor 1515 and IL-4 can both cross-compete for binding to the IL-13 receptor complex (Hilton et al., 1996; Miloux et al., 1996). In addition, the c, a component of the type 1 IL-4R, appears to compete for the IL-4R chain and inhibit IL-13 binding by sequestering the IL-4R chain (Orchansky et al., 1997; Kuznetsov 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 coexpressed.

Relevant homologies and species differences See Table 1. It is also of note that both human and mouse IL-13 receptors share approximately 25% identity to the IL-5R chain.

Affinity for ligand(s)

Cell types and tissues expressing the receptor See Table 3.

Regulation of receptor expression Studies on mature human B cells found that potent B cell activators, such as the antibodies anti- or antiCD40, upregulated IL-13R1 mRNA expression, especially when they were used to co-stimulate B cells (Graber et al., 1998; Ogata et al., 1998; Ford et al., 1999). In addition, the expression of hIL-13R1 mRNA on human peripheral T cells was shown to be downregulated after stimulation by either anti-CD3 plus anti-CD28 or anti-CD3 plus PMA (Gauchat et al., 1997). The activation of human monocytes by IL-13 results in the downregulation of IL-13R1 (Graber et al., 1998).

Release of soluble receptors

See Table 2.

Table 1 Percentage of shared amino acid identity between the IL-13-binding chains huIL13R1

huIL13R2

mIL13R1

mIL13R2

huIL-13R1

100%

27%

74%

26%

huIL-13R2

27%

100%

25%

59%

mIL-13R1

74%

25%

100%

29%

mIL-13R2

26%

59%

29%

100%

In humans, soluble IL-13R1 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 subsequent partial sequencing of the protein indicate that it is the soluble form of mIL-13R2 protein (Zhang et al., 1997).

SIGNAL TRANSDUCTION

Associated or intrinsic kinases Although the IL-13R1/IL-4R 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-13R1

IL-13R2

IL-13R1

IL-13R2

sIL-13R2

Mr

70,000

70,000

60,000

70,000

40,000

Mature peptide

401 aa

354 aa

398 aa

362 aa

n.k.

Precursor peptide

427 aa

380 aa

424 aa

383 aa

n.k.

Glycosylation sites

10

4

4

4

n.k.

Affinity Kd

4 nM

450 pM

2±10 nM

250 pM

35 pM

+IL-4R

30 pM

n.c.

75 pM

n.c.

±

n.c., no change; n.k., not known; sIL-13R2, soluble IL-13R2.

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-13R1

mIL-13R1

hIL-13R2

mIL-13R2

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 receptor has been shown to phosphorylate JAK2 and TYK2 in fibroblasts (Murata et al., 1998), JAK1, TYK2 in B9 cells (Welham et al., 1995), JAK1 in TF-1 cells (Keegan et al., 1995), JAK1, JAK2 and TYK2 in monocytes (Roy and Cathcart, 1998) and colon carcinoma cell lines (Murata et al., 1996). Partial deletion analysis of the cytoplasmic domain of IL13R1 cells has noted that the terminal 38 amino acids were not necessary for proliferation or for the tyrosine phosphorylation of JAK1 or TYK2 in FD5 cells (Orchansky et al., 1999). There is no evidence that JAK3 kinase is involved in IL-13 signal transduction (Keegan et al., 1995).

Cytoplasmic signaling cascades The IL-13R initiates a JAK/STAT signaling cascade resulting in the activation of STAT6 (Lin et al., 1995) and STAT3 (Orchansky et al., 1999) and which may

be downregulated by SOCS proteins (Starr et al., 1997). In addition, IL-13 also induces the phosphorylation of IRS-1/2 and IL-4R (Keegan et al., 1995) and activates PI-3 kinase (Wright et al., 1999). In human monocytes, IL-13 has been described as inducing cAMP production, PLC 1 activation, phosphoinositol metabolism, and mobilization of intracellular calcium stores (Sozzani et al., 1998). The tyrosine phosphatase SHP-1 has been implicated in the negative regulation of IL-13 signal transduction (Haque et al., 1998).

DOWNSTREAM GENE ACTIVATION

Transcription factors activated STAT6 is activated upon IL-13 receptor activation and is an important mediator of IL-13 function

IL-13 Receptor 1517 (Lin et al., 1995; Palmer-Crocker et al., 1996). STAT3 has also been reported to be activated by IL-13 (Orchansky et al., 1999). The transcription factors c-fos, c-jun, and c-myc have also been shown to be upregulated by IL-13 (Doucet et al., 1998).

Genes induced Notable genes induced or upregulated by IL-13 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 fibroblasts (Doucet et al., 1998) and endothelial cells (Kotowicz et al., 1996).

Promoter regions involved A STAT6 response element has been described in the IL-4 promoter GTCTGATTTCAGGAACAATTTTA (Curiel et al., 1997).

BIOLOGICAL CONSEQUENCES OF ACTIVATING OR INHIBITING RECEPTOR AND PATHOPHYSIOLOGY

Human abnormalities There have not been cases described where either IL-13 receptor has been directly implicated in a human abnormality; however, in certain cases some polymorphisms in the IL-4R chain have been shown to be associated with atopy (Hershey et al., 1997; Mitsuyasu et al., 1998). The IL-13R has been found to be overexpressed and a marker for human gliomas (Debinski et al., 1999a,b).

THERAPEUTIC UTILITY

Effect of treatment with soluble receptor domain There are no published work describing the effects of using the soluble IL-13 receptor for therapeutic purposes in humans. In mice, treatment with a recombinant soluble IL-13R2-Fc fusion protein impaired the expulsion of nematode worms (Urban et al., 1998). A soluble form of the mIL-13R1 has also been administered to mice and found to increase the production of IgG2a and IgG2b in germinal center B cells (Poudrier et al., 1999).

Unique biological effects of activating the receptors

Effects of inhibitors (antibodies) to receptors

In humans, only IL-4 and IL-13 have been reported to induce antibody class-switching to IgE (Punnonen et al., 1993), which is a major mediator of allergic responses. Therefore, IL-13 and its receptor are likely to have an important role in the pathology of atopy. In mice, IL-13 has been demonstrated to play a unique role in inducing the rapid expulsion of certain nematode worms, suggesting an important role for IL-13 in gut immunology (McKenzie et al., 1998b).

There is no published works describing the effects of using anti-IL-13 receptor antibodies for therapeutic purposes. However, the mutant form of human IL-4, Y124D, is a potent antagonist of both IL-4 and IL-13 (Kruse et al., 1992; Aversa et al., 1993; Matthews et al., 1997) and may have therapeutic potential. Some antibodies to the IL-4R chain have been shown to inhibit B cell responses to both IL-4 and IL-13 (Zurawski et al., 1995; Matthews et al., 1997).

Phenotypes of receptor knockouts and receptor overexpression mice

References

As yet, neither IL-13R molecules have been knocked out. However, mice deficient in both the IL-4R chain (Barner et al., 1998) and STAT6 (Takeda et al., 1996) have been generated and these mice have impaired TH2 cell development and fail to expel nematode infections efficiently (Urban et al., 1998). These results are in concordance with findings for IL-13-deficient mice (McKenzie et al., 1998b).

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