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Ludwig Institute for Cancer Research, Brussels Branch and the Experimental Medicine Unit, Christian de Duve Institute of Cellular Pathology, Université de Louvain, Brussels, Belgium
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, IFN-
, IL-10, and IL-10-related T cell-derived inducible
factor/IL-22. By screening genomic DNA databases, we identified a gene
encoding a protein of 231 aa, showing 33 and 34% amino acid identity
with the extracellular domains of the IL-22 receptor and of the
IL-20R/cytokine receptor family 2-8, respectively, but lacking the
transmembrane and cytoplasmic domains. A lower but significant sequence
identity was found with other members of this family such as the IL-10R
(29%), cytokine receptor family 2-4/IL-10R (30%), tissue factor
(26%), and the four IFN receptor chains (23–25%). This gene is
located on chromosome 6q24, at 35 kb from the IFNGR1
gene, and is expressed in various tissues with maximal expression in
breast, lungs, and colon. The recombinant protein was found to bind
IL-10-related T cell-derived inducible factor/IL-22, and to inhibit the
activity of this cytokine on hepatocytes and intestinal epithelial
cells. We propose to name this natural cytokine antagonist IL-22BP for
IL-22 binding protein. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The IL-22R complex consists of two chains that are each able to bind
IL-22: cytokine receptor family
(CRF)2 2-4 and CRF2-9
(3, 5). CRF2-4 is also called IL-10R because it is
required for IL-10 signaling (6). CRF2-9 was originally
described as an orphan receptor called ZCYTOR11 in patent databases and
proposed to be renamed IL-22R by Xie et al. (3). Both
chains belong to the class II cytokine receptor family
(7). This family consists of eight members, including two
pairs of two receptor subunits for either type I (IFN-, IFN-,
IFN-
, and IFN-
) and type II (IFN-) IFNs, the IL-10R, the
IL-22R/CRF2-9, the IL-10R/CRF2-4, the IL-20R/CRF2-8, and tissue
factor (TF) (7, 8). These receptors are almost exclusively
related by their extracellular domain, which have tandem fibronectin
type III (FNIII) domains. Four of the corresponding genes,
IFNAR1, IFNAR2, IL10R2, and
IFNGR2 are clustered on human chromosome 21;
IFNGR1 and the CRF2-8 gene map to
chromosome 6; TF and IL22R are located on
chromosome 1; and IL10R1 is on chromosome 11.
By screening public DNA databases for homology with the extracellular domains of type II cytokine receptors, we characterized a new member of this family. The putative protein is homologous to the extracellular domain of type II receptors, but has no transmembrane and cytoplasmic domains. This new soluble receptor is able to interact with IL-22 and to block IL-22 activity.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A search for homology was performed with the protein sequence of the extracellular domain of the IL-10R using the TBLASTN software to screen the database of the Sanger Center (http://www.sanger.ac.uk/cgi-bin/nph-Blast_server;html). Two short regions of homology were found in a bacterial artificial chromosome (BAC) clone from chromosome 6q24 and this BAC clone was further analyzed by the NIX analysis program (http://www.hgmp.mrc.ac.uk/Registered/Webapp/nix/) developed by the United Kingdom Human Genome Mapping Project Resource Center. A phylogenetic tree was generated by multiple alignment of the extracellular domains of the class II cytokine receptors using the CLUSTAL X Multiple Sequence Alignment program (9) available on the web (http://www-igbmc.u-strasbg.fr./BioInfo/ClustalX/Top.html).
Cell cultures, transfections, and cytokines
H4IIE rat hepatoma cells and HT-29 human intestinal epithelial cells were grown in DMEM supplemented with 10% FCS, 0.55 mM L-arginine, 0.24 mM L-asparagine, and 1.25 mM L-glutamine. HEK293-EBNA human embryonic kidney cells were grown in DMEM supplemented with 10% FCS. The RAW264.7 cells were cultured in DMEM supplemented with 5% FCS (Myoclone Super Plus bovine serum; Life Technologies, Gent, Belgium).
Recombinant human IL-22 was produced in Escherichia coli as
follows. The IL-22 sequence (corresponding to aa Q29-I179) was
amplified by PCR from a cDNA clone using primers hTIFa
(5'-GGCCCTCTTGGTACATATGCAGGGAGGAGCAGCTGCG-3') and hTIFb
(5'-CAGCTTTGCTCTGGGGATCCTTATCAAATGCAGGCATTTCTCAG-3'). The PCR
product was digested with NdeI and BamHI and
cloned into the pET3A plasmid (Stratagene, La Jolla, CA). E.
coli strain BL21-codon plus-(DE3)-RIL (Stratagene) was used as the
expression host. The cells were grown in Luria-Bertani medium
supplemented with ampicillin (100 µg/ml) and chloramphenicol (34
µg/ml). Expression of IL-22 was induced with 1 mM
isopropyl--D-thiogalactoside at a cell
density (600 nm) of 
1. Cells were collected by centrifugation 4
h after induction. The cell pellet was disrupted with a high-pressure
cell homogenizer and the IL-22 inclusion bodies were collected by
centrifugation. Inclusion bodies were washed extensively first with 50
mM Tris-HCl,100 mM NaCl, 1 mM EDTA, 1 mM DTT, 0.5% sodium deoxycholate
(w/v; pH 8), and finally with the same buffer without detergent.
Inclusion bodies were solubilized overnight at 4°C in 8 M urea, 50 mM
2-(N-morpholino)ethanesulfonic acid, 10 mM EDTA, and
0.1 mM DTT (pH 5.5). The solution was centrifuged for 1 h at
100,000 x g and the supernatant was stored at -80°C
until use. The purity of the IL-22 was estimated at around 80% based
on SDS-PAGE and Coomassie blue staining analysis. The concentration of
protein was estimated by UV absorbance in urea solution using a
calculated 
280 = 3840. The IL-22 protein was
refolded by direct dilution of the solubilized inclusion bodies in the
following folding mixture: 100 µg/ml IL-22, 100 mM Tris-HCl, 2 mM
EDTA, 0.5 M L-arginine, 1 mM reduced glutathione,
and 0.1 mM oxidized glutathione (pH 8). The solution was incubated for
72 h at 4°C. The folding mixture was then concentrated by
ultrafiltration in an Amicon chamber with a YM3 membrane before
purification on a Superdex75 (Amersham Pharmacia Biotech, Piscataway,
NJ) gel filtration column. The protein was eluted with 25 mM
2-(N-morpholino)ethanesulfonic acid and 150 mM NaCl (pH
5.4).
For transient expression, the CRF2-X and CRF2-X-Ig cDNAs were cloned into pCEP4 plasmid (Invitrogen, Groningen, The Netherlands) under the control of the CMV promoter. HEK293-EBNA cells were seeded in six-well plates (Nunc, Roskilde, Denmark) at 8 x 105 cells/well 1 day before transfection. Transfections were conducted using the LipofectAMINE method (Life Technologies) according to the manufacturer’s recommendations with 2 µg of plasmid DNA. After transfection, cells were incubated in 1.5 ml of normal medium for 3 days for maximal production of recombinant human CRF2-X or CRF2-X-Ig. Human IL-10 was purchased from PeproTech (London, U.K.).
Luciferase assays
The IL-22 response was assessed by measuring luciferase
production by cells transfected with the pGRR5 construct, (provided by
Dr. P. Brennan, Imperial Cancer Research Fund, London, U.K.). This
construct contains five copies of the STAT binding site of the FcRI
gene inserted upstream from a luciferase gene controlled by the
thymidine kinase (TK) promoter. As an internal control, we used the
pRL-TK vector (Promega, Madison, WI) containing the Renilla
luciferase gene under the control of the TK promoter. Recombinant IL-22
was preincubated for 1 h with CRF2-X or CRF2-X-Ig (5% HEK293 cell
supernatant) or control medium (5% supernatant from mock-transfected
HEK293 cells), in 24-well plates. A total of 107
H4IIE or HT-29 cells was electroporated with 15 µg of pGRR5 and with
1 µg of pRL-TK (250 V, 192 
, 1, 200 µF) and seeded at 4 x
105 cells/well. RAW264 cells were transfected
under the same conditions, except for the resistance (74 ). Two
hours later, cells were pelleted and lysed. Luciferase activity was
monitored with the Dual-Luciferase Reporter Assay System kit (Promega).
Alternatively, transfected cells were seeded in 96-well plates at
105 cells/well, and luciferase activity was
measured after 2 h with the Luclite plus Assay System kit
(Canberra-Packard, Meriden, CT) using a Top Count microplate
scintillation counter (Canberra-Packard).
RT-PCR of CRF2-X and generation of an IgG3 fusion protein
Total RNA was isolated from various organs using guanidinium isothiocyanate lysis and CsCl gradient centrifugation (10). Reverse transcription was performed on 5 µg of total RNA with an oligo(dT) primer. cDNA corresponding to 5 ng of total RNA was amplified for 37 cycles by PCR with specific primers for CRF2-X as follows: sense, 5'-AGGGTACAATTTCAGTCCCGA-3' and antisense, 5'-CGGCGTCATGCTCCATTCTGA-3'. Annealing temperature was 55°C. The PCR products were analyzed in ethidium bromide-stained 1% agarose gels.
The predicted full-length cDNA was amplified by RT-PCR from breast tissue RNA using oligonucleotides derived from sequences of exons 1 and 5: sense primer, 5'-TGAACAGTCACACTCGAGACCATGATGC-3', and antisense primer, 5'-CATCCTGTTCTCGAGGAGCTTTAGA-3'. Both oligonucleotides had mutations that introduce a XhoI site to allow direct cloning into the pCEP4 plasmid (Invitrogen) under the control of the CMV promoter.
The CRF2-X-Ig fusion cDNA was produced as follows: human CRF2-X was amplified from the pCEP4-CRF2-X construct using a sense primer on pCEP4 and an antisense primer on CRF2-X, in which the STOP codon was mutated by introducing a BclI restriction site: 5'-CCAAATTCCATGATCAATGGAATTTCCACACATCTCT-3'. The region comprising the hinge, CH2, and CH3 domains of the murine IgG3 isotype heavy chain was amplified from the IgG3 anti-2,4,6-trinitrophenyl hybridoma C3110 with the following primers: sense, 5'-AAGACTGAGTTGATCAAGAGAATCGAGCCTAGA-3' and antisense, 5'-AATGTCTAGATGCTGTTCTCATTTACC-3' containing BclI and XbaI sites for cloning. After amplification, both PCR products were digested and cloned into pCEP4 plasmid (Invitrogen). Clones that contained the CRF2-X-Ig fusion cDNA were sequenced with an automated fluorescence-based system (Applied Biosystems 310; Applied Biosystems, Foster City, CA) using the Applied Biosystems Prism BigDye Terminator Cycle Sequencing Ready Reaction kit (PE Biosystems, Foster City, CA). The IL-22R-Ig fusion was produced as follows: the extracellular part of human IL-22R was amplified with a specific sense primer: 5'-AGGGAAAGCTTTGTGCCAGCCCCGATGAG-3' containing a restriction site for HindIII and a specific antisense primer in which the STOP codon was mutated by introducing a BclI restriction site: 5'-GGTCCTGATCAGGTCTGGCAGTGTCTTCA-3'. The PCR products were digested and cloned in fusion with the IgG3 fragment described above into pcDNAI/Amp plasmid (Invitrogen). The production of IL-9-Ig fusion protein was described previously (11).
IL-22 interaction assay
Specific interactions between IL-22 and IgG3 fusion proteins were assessed by ELISA as follows. Reacti-Bind Maleic Anhydride Activated Polystyrene plates (Pierce, Rockford, IL) were coated with 100 µg/ml recombinant human IL-22 or 200 µg/ml BSA in PBS overnight at 4°C. After washing in PBS buffer containing Tween 20 (0.01%), the plate was blocked with BSA (1% in PBS) for 2 h, followed by incubation with 50 µl of supernatant of transiently transfected HEK293 cells for 2 h at 37°C. Bound CRF2-X-Ig was detected by using anti- mouse Ig polyclonal Abs coupled to peroxidase (Transduction Laboratories, Lexington, KY). The enzymatic activity was measured by adding 100 µl of 3,3',5,5'-tetramethylbenzidine (Calbiochem, Darmstadt, Germany) and the reaction was stopped by 20 µl of 2 M H2SO4 before reading the absorbance at 450 nm.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To identify putative new members of the class II cytokine receptor
family, which includes receptors for IFNs and IL-10, we screened the
database of the Sanger Center with the protein sequence of the
extracellular domain of the IL-10R. Two short regions of homology were
found in a BAC clone from chromosome 6q24 (GenBank accession number
AL05337) at 40 kb from the IFNGR1 gene. One fragment
showed 40% amino acid identity with residues 63–119 of the IL-10R,
and the second fragment, located 3-kb upstream showed 47% identity for
residues 29–47, suggesting the presence in this region of an
IL-10R-related gene, which we provisionally designated CRF2-X.
This BAC sequence was further analyzed using the NIX analysis program
developed by the United Kingdom Human Genome Mapping Project Resource
Center. This software predicted five exons stretching over 16 kb,
the last exon corresponding to several expressed sequence tag
sequences. The genomic organization and the intron-exon junctions were
confirmed by a series of RT-PCR using oligonucleotides located in the
predicted exons. Using breast RNA as a template, we amplified a cDNA
fragment of 775 nts, including a 693-bp open reading frame that encodes
a 231-aa protein of 27 kDa. The putative CRF2-X protein contains a
stretch of hydrophobic residues at the N terminus, compatible with a
signal peptide, and shows a significant sequence homology with the
extracellular domains of the IL-10R family. However, in contrast to
these receptors, CRF2-X lacks a hydrophobic transmembrane domain,
suggesting that it is a secreted protein. Protein alignment showed 33
and 34% amino acid identity with the extracellular domain of the
IL-22R (Fig. 1
A) and with that
of the IL-20R/CRF2-8, respectively. A lower but significant sequence
identity was found with other members of this family such as IL-10R
(29%), CRF2–4/IL-10R (30%), tissue factor (26%), and the four
IFN receptor chains (23–25%). The predicted mature protein contains
four cysteines that are conserved in most members of the class II
cytokine receptors. The CRF2-X protein also contains five potential
N-linked glycosylation sites. A phylogenetic tree of the
extracellular sequences from the class II cytokine receptors is shown
in Fig. 1B and confirmed that CRF2-X is particularly related
to IL-22R.
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, along with the IFNGR1 gene,
which is located in the same orientation and ends at 35 kb upstream
from CRF2-X. This gene contains five exons. Exon I encodes the signal
peptide and the four succeeding exons encode the mature protein. The
expression of the CRF2-X gene was analyzed by RT-PCR with
oligonucleotides located in exons 2 and 3 (Fig. 3). The strongest expression was found in
breast, and a clear signal was also detected in lungs and in the
intestinal tract (stomach and colon), Skin, testis, brain, heart, and
thymus were also positive but either at lower levels or in some samples
only. No detectable expression was found in prostate, bladder, kidney,
ovary, muscle, bone marrow, liver, and uterus. Interestingly, in some
tissue samples such as skin and lungs in Fig. 3, a second band was
detected by the RT-PCR amplification. This PCR product was sequenced
and turned out to correspond to an alternative splicing product,
including an additional 96-bp exon located between exons 2 and 3 (Fig. 2). This results in an insertion of 32 aa between residues
Ile66 and Tyr67.
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The observation that CRF2-X is mostly related to the extracellular
domain of the IL-22R led us to test the hypothesis that this protein
binds IL-22. We produced a CRF2-X-Ig fusion protein by transient
tranfection of HEK293 cells. Microtiter plates were coated with
recombinant IL-22 or BSA and incubated with the supernatant of cells
transfected with the CRF2-X-Ig, IL-9-Ig, and IL-22R-Ig cDNAs or with an
empty vector. The interaction was checked with an anti-Ig Ab. As
shown in Fig. 4, CRF2-X-Ig bound to
IL-22-coated plates but not to plates coated with BSA. As expected,
IL-22R-Ig, but not IL-9-Ig, also bound specifically to IL-22.
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We assessed the ability of CRF2-X to block IL-22 biological
activity by using two IL-22-responsive cell lines: H4IIE and HT-29. The
H4IIE rat hepatoma cell line responds to IL-22 by activation of STAT
transcription factors and acute phase reactant production. HT-29, an
intestinal epithelial cell line, shows STAT3 activation in response to
IL-22 (L. Dumoutier and J. C. Renauld, unpublished results). In
both cell lines, IL-22-induced STAT activation can be monitored after
transfection with a luciferase reporter construct that includes five
STAT binding sites in addition to a minimal TK promoter
(4). Transfected cells were stimulated with IL-22 in the
presence of supernatants from cells transfected with the CRF2-X cDNA.
As shown in Fig. 5, the effect of IL-22
(4 ng/ml) on HT-29 was completely blocked by both CRF2-X- and
CRF2-X-Ig-containing supernatants. Similar results were obtained on
H4IIE cells. By contrast, the effect of IL-6 in the same assay was not
affected (data not shown). The effect of CRF2-X on IL-10 activity was
analyzed on the RAW264 mouse macrophage cell line. Using the same
STAT-dependent luciferase assay as above, we failed to detect any
inhibition of IL-10, as illustrated in Fig. 6.
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). Decreasing CRF2-X
concentrations led to a loss of the inhibitory effect, but did not
allow us to unmask any potentiating activity for IL-22 (data not
shown). It has been shown for the IL-4R that the soluble and
transmembrane forms have similar association rates, whereas the soluble
form has a faster dissociation rate. Thus, IL-4/IL-4 binding protein
(BP) complexes must be transient and reversible, allowing the ligand to
dissociate from one soluble receptor and to become available for
binding to another IL-4BP or to a membrane IL-4R from which it would
dissociate less likely (13). We therefore tested the
hypothesis that CRF2-X could delay rather than inhibit IL-22 activity.
The effect of IL-22 on HT-29 cells was maximal after 4–6 h and
dramatically decreased at 24 h, but CRF2-X had the same inhibitory
effect throughout the assay, indicating that it could not delay IL-22
activity in vitro (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Unlike these soluble forms of cytokine receptors, IL-22BP has no membrane-bound counterpart and is more related to genes such as IL18BP and osteoprotegerin, which code for secreted antagonists of IL-18 and osteoprotegerin ligand, respectively (17, 18). The type II IL-1R is another example of a putative decoy receptor for cytokines, although the latter molecule can either be released or remain associated to the cell membrane, where it can associate with one of the two subunits of the functional IL-1R (19). IL-18BP has been proposed to be a pure IL-18 antagonist because of its high affinity for IL-18. This contrasts with most soluble cytokine receptors that show lower affinity than their membrane-bound counterpart. Indeed, cellular receptor complexes are often composed of at least two subunits and can have a greater affinity than their ligand-binding subunits alone. Additional experiments are needed to assess the respective affinities of IL-22 for its cellular receptor and IL-22BP.
IL-22BP is a new member of the class II cytokine receptors. The extracellular part of these receptors has two tandem FNIII domains, although one of the subunits of the type I IFN receptor complex has four tandem FNIII domains. Their intracellular domains vary in length and do not demonstrate any sequence similarity. The genes encoding four receptor chains are clustered on human chromosome 21 (IFNAR1, IFNAR2, IL10R2, and IFNGR2). TF and IL22R are located on chromosome 1 and IL10R is encoded on chromosome 11. Here, we identified the IL22BP gene from a BAC clone on chromosome 6q24, close to IFNGR1 and the gene encoding the IL-20R/CRF2–8. Based on the sequence, IL-22BP is mostly related to IL-22R, but the same range of similarity is found with other members of the family, raising the possibility that IL-22BP could bind to other IL-10-related cytokines as well. However, we show here that IL-22BP does not block IL-10 activities. In this respect, the homology between IL-22BP and IL-20R/CRF2-8 raises the possibility that IL-22BP binds to IL-20 as well. However, preliminary experiments indicate that IL-20 fails to compete with IL-22 for binding to IL-22BP, suggesting that the interaction is limited to IL-22.
Surprisingly, many tissues expressing IL-22BP show two mRNA variants generated by alternative splicing. The larger variant contains an insertion of 96 nts in the coding region. Preliminary experiments suggest that this variant is less efficiently secreted and fails to block IL-22 activity. However, additional experiments are needed to determine whether the resulting protein is a low-affinity IL-22BP or could exert distinct activities. This alternative splicing process might also represent a posttranscriptional mechanism of regulation for IL-22BP production.
Little is known about the biological activities of IL-22. This cytokine is produced by activated T cells and upon LPS injection in vivo. The only IL-22 activity described so far is the up-regulation of acute phase reactant production by hepatocytes (4). Beside hepatocytes, other cell types such as intestinal and lung epithelial cells respond to IL-22 (Ref. 3 and unpublished results from our laboratory), suggesting that IL-22 might have pleiotropic activities during inflammatory or immune responses. Although most soluble cytokine receptors are expressed at low levels under resting conditions, their production is often enhanced by activation of T cells or monocytes (14, 15, 20). Soluble receptors are also sometimes induced by their own ligand as a negative feedback mechanism (14, 15). It is therefore possible that IL-22BP production is also inducible under particular circumstances. However, we failed to detect any IL-22BP induction in IL-22-stimulated cells or in peripheral mononuclear cells stimulated by LPS or anti-CD3 Abs. So far, the main and most reproducible expression of IL-22BP was found in breast tissue but further investigations will be necessary to better characterize its cellular source as well as potential association of abnormal IL-22BP production with physiopathological situations. Preliminary data indicate that the IL22BP gene is conserved in the mouse. The characterization of the murine IL22BP gene is in progress and will allow us to study the activity and expression of this protein in various in vivo models.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: CRF, cytokine receptor family; TF, tissue factor; TK, thymidine kinase; FNIII, fibronectin III, BAC, bacterial artificial chromosome; BP, binding protein; iL-TIF, IL-10-related T cell-derived inducible factor.
Received for publication January 23, 2001. Accepted for publication April 2, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) is a shared component of both IL-10 and IL-TIF (IL-22) receptor complexes. J. Biol. Chem. 276:2725.ner, U., H. Blum, M. Schnare, M. Röllinghoff, A. Gessner. 2000. A soluble form of the murine common chain is present at high concentrations in vivo and suppresses cytokine signaling. Blood 97:183.This article has been cited by other articles:
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