IL-10 Receptor

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by  de Waal Malefyt R.

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: [phone], fax: [phone], 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
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