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*
Department of Molecular Genetics and Microbiology, University of Medicine and Dentistry, Robert Wood Johnson Medical School, Piscataway, NJ 08854; and
Division of Therapeutic Proteins, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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R1 receptor in
which the IL-22R1 intracellular domain was replaced with the IFN-R1
intracellular domain. In these cells, IL-22 activates biological
activities specific for IFN-, such as up-regulation of MHC class I
Ag expression. The addition of IL-22BP neutralizes the ability of IL-22
to induce Stat activation and MHC class I Ag expression in these cells.
Thus, the soluble receptor designated IL-22BP inhibits IL-22 activity
by binding IL-22 and blocking its interaction with the cell surface
IL-22R complex. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, preventing
ligand binding to the signal-transducing IL-1RI. It may also act by
sequestering the IL-1 AcP and, thus, reducing its availability for the
functional IL-1R complex. In contrast, the IL-18-binding protein (BP)
does not possess a transmembrane domain and functions as a soluble
inhibitor of IL-18 actions. The use of decoy or soluble receptors for
cytokines using members of the class II CRF for signaling
(3) has been demonstrated only for IFN-
. The human
IFN-R2c, one of the functional chains of the IFN-R complex, has
two splice variants, the membrane bound IFN-R2b with a short
intracellular domain, which appears unable to transduce the signal, and
the soluble IFN-R2a form (6, 11, 12, 13, 14, 15, 16). However, the
functions of these receptors have not been well characterized. IL-22 (or IL-10-related T cell-derived inducible factor) is a member of the family of IL-10 homologues and requires two receptor chains to assemble the functional IL-22R complex, the unique IL-22R1 chain and the IL-10R2c chain (17, 18), which also serves as a second chain of the IL-10R complex (19). Both chains belongs to the class II CRF (3). The other family members are two receptor chains for type I IFNs, two receptor chains for type II IFNs, another chain of the IL-10R complex, and tissue factor. Several orphan receptors from this family have also been identified (3). The IL-22R complex demonstrates unique features compared with other receptor complexes in that both chains are able to bind IL-22 independently, whereas other ligands (type I and II IFNs and IL-10) bind with high affinity to only one chain of the corresponding receptor complexes, with the second chain only slightly modulating affinity of the entire receptor complex (reviewed in Ref. 3). In a search of novel receptors from the class II CRF, we identified and cloned a soluble receptor designated CRF class II member 10 (CRF2-10) or IL-22BP, which is the topic of this report. We show that CRF2-10 binds to IL-22, prevents its interaction with the functional IL-22R complex, and, thus, blocks the activity of IL-22.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Primers 5'-CAATGGAAAAATAAAGAAGACTGTTGG-3' (R10-1 forward (F) primer, R10-1F), 5'-GGTACTCAAGAACTCTCTTGTGACC-3' (R10-2F), 5'-TACTCTTAATTCATCGCCCTCTCCAC-3' (R10-5 reverse (R) primer, R10-5R), 5'-CTTCAGGACTACTGAATTGCATTCAC-3' (R10-6R) and a library containing cDNA isolated from human placenta (catalog number HL4025AH, Clontech Laboratories, Palo Alto, CA) were used for nested PCR. The first round was performed with R10-1F and R10-6R primers followed by the second round with R10-2F and R10-5R primers and the PCR product of the first round as a template. The resultant PCR product was cloned and sequenced. Three additional primers, 5'-GGTCACAAGAGAGTTCTTGAGTACC-3' (R10-9R), 5'-TCTGAGTAGCTCCCAGCCGAGGCCG-3' (R10-10R), and 5'-GTAATAAGGTTCCTGTATGTCTGAGG-3' (R10-11R), were designed to clone the 5' end of the CRF2-10 cDNA. Nested PCR was performed with these three primers and adapter primers (AP)1 and 2 and placental cDNA provided with the Marathon cDNA amplification kit (catalog number K1802-1, Clontech Laboratories) following the manufacturer’s protocol. The first round was performed with the R10-10R primer and AP1 and was followed by the second round with either the R10-11R or R10-9R primer and AP2 and the PCR product of the first round as a template. Several PCR products were obtained and sequenced.
CRF2-10-specific primers 5'-AGGAACACTGGTTGCCTGAACAGTC-3' (R10-22F), 5'-TGGGGATCCAGGAACTCAGTCAACGCATGAGTC-3' (R10-25F), 5'-ACGAGTCATCCTGTTCTCAGGGAGC-3' (R10-16R), and 5'-CAGAATTCATGGAATTTCCACACATC-3' (R10-18R) were designed to clone a fragment of the CRF2-10 cDNA encoding the mature protein into the pEF-SPFL vector (20). These primers and either the library containing cDNA isolated from human placenta or cDNAs synthesized with total RNA isolated from LPS-stimulated PBMCs obtained from a healthy donor were used for nested PCR. The first round was performed with R10-22F and R10-16R primers followed by the second round with R10-25F and R10-18R primers and the PCR product of the first round as a template. Several PCR products were purified and sequenced. The PCR product corresponding to the intact CRF2-10 protein was digested with BamHI and EcoRI restriction endonucleases and cloned into corresponding sites of the pEF-SPFL vector (20), resulting in plasmid pEF-SPFL-CRF2-10. This plasmid encodes CRF2-10 tagged at its N terminus with the FLAG epitope (FL-CRF2-10).
To clone the extracellular domain of the CRF2-8 protein (or ZCYTOR7, GenBank accession number XM004438) (3), primers 5'-GGGACTGAGCAGTCTGCTGCCC-3' (R8-1F), 5'-GCCGGATCCCTGTGTCTCTGGTGG-3' (R8-2F), 5'-ACACGGTAATAGATATGGGC-3' (R8-3R), and 5'-CCGAATTCTATTTAGCCTTGAACTCT-3' (R8-4R) and the library containing cDNA isolated from human placenta were used for nested PCR. The first round was performed with R8-1F and R8-3R primers followed by the second round with R8-2F and R8-3R primers and the PCR product of the first round as a template. The resulting PCR product was digested with BamHI and EcoRI restriction endonucleases and cloned into corresponding sites of the pEF-SPFL vector (20), resulting in plasmid pEF-SPFL-CRF2-8. This plasmid encodes CRF2-8 tagged at its N terminus with the FLAG epitope (FL-CRF2-8).
The construction of the FLAG-tagged phosphorylatable (P) IL-22 was described previously (17), and the nucleotide sequences of the modified regions of all constructs were verified in their entirety by DNA sequencing.
Cells, transfection, and cytofluorographic analysis
The 16-9 hamster x human somatic cell hybrid line is the Chinese hamster ovary cell K1 hybrid containing a translocation of the long arm of human chromosome 6 encoding the human IFNGR1 gene and a transfected human HLA-B7 gene (21). The cells were maintained in F12 (Ham) medium (Sigma, St. Louis, MO) containing 5% heat-inactivated FBS (Sigma). COS-1 cells, an SV40-transformed fibroblast-like simian CV-1 cell line, were maintained in DMEM (Life Technologies, Rockville, MD) with 10% heat-inactivated FBS. Cells were transfected as previously described (19, 20). COS-1 cell supernatants were collected at 72 h as a source of the expressed proteins.
To detect cytokine-induced MHC class I Ag (HLA-B7) expression, cells were treated with COS-1 cell supernatants or purified recombinant proteins as indicated in the text for 72 h and analyzed by flow cytometry. Cell surface expression of the HLA-B7 Ag was detected by treatment with mouse anti-HLA (W6/32) (22) mAb followed by FITC-conjugated goat anti-mouse IgG (Santa Cruz Biotechnology, Santa Cruz, CA). The cells then were analyzed by cytofluorography as previously described (13).
EMSAs and Western and Northern blotting
Cells were starved overnight in serum-free medium and then
treated with IL-10 or IL-22 for 15 min at 37°C and used for EMSA
experiments to detect activation of Stat1, Stat3, and Stat5 as
previously described (19). EMSAs were performed with a
22-bp sequence containing a Stat1- binding site corresponding to the
IFN- activation sequence element in the promoter region of the human
IFN regulatory factor-1 gene (5'-GATCGATTTCCCCGAAATCATG-3') as
previously described (12, 23).
Three days after transfection, conditioned medium from COS-1 cells transiently transfected with expression plasmids was collected. FLAG-tagged proteins in the conditioned medium were identified by Western blotting with anti-FLAG epitope-specific M2 mAb (Sigma) as previously described (20). FLAG-tagged proteins were purified from conditioned medium by immunoaffinity chromatography with the anti-FLAG M2 gel (Sigma) according to the manufacturer’s suggested protocols.
Northern blotting was performed as described previously
(17) with suppressors of cytokine signaling (SOCS)-3 or
-actin probes.
Cross-linking
The FLAG-tagged P human IL-22 (FL-IL-22-P) was labeled with [32P]ATP and used for cross-linking to cells as previously described (17, 23, 24, 25). [32P]FL-IL-22-P and soluble receptors were mixed in 200 µl PBS and incubated at 22°C for 1 h followed by the addition of bis(sulfosuccinimidyl)suberate to the final concentration 0.5 mM. The reaction mixture was incubated at 22°C for 10 min. and Tris-HCl buffer (pH 8.0) was added to the final concentration at 50 mM for 10 min. The complexes were later analyzed on SDS-PAGE.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A search of the GenBank database with the TBLASTN program for possible IL-22R1 (CRF2-9) homologues revealed a genomic fragment from human chromosome 6 contained within a bacterial artificial chromosome (BAC) (GenBank accession number AL050337) potentially encoding a fragment of a protein with homology to IL-22R1. We hypothesized that this genomic fragment represented an exon of a novel receptor with homology to IL-22R1. Further analysis of the BAC sequence revealed that several expressed sequence tags (ESTs) were positioned in proximity to this hypothetical exon. These ESTs represented the 3' untranslated region (UTR) of a cDNA with the UniGene designation Hs.126891 consisting of a group of related ESTs. We speculated that the exon identified in the homology search is a part of the Hs.126891 gene.
Two sets of primers were designed for PCR: the sequences of primers
R10-1 and R10-2 were derived from the identified hypothetical exon
sequence, and the sequences of primers R10-5 and R10-6 were derived
from the 3' UTR sequence (see Materials and Methods). The
primers and the human placental cDNA library were used for nested PCR.
The resultant PCR product was cloned and sequenced. The analysis of the
sequence revealed the presence of an additional exon (exon 5; Fig. 1
; exons are numbered based on the
structure of the CRF2-10 gene) between exon 4 (primers R10-1 and R10-2)
and exon 6 (primers R10-5 and R10-6) containing the entire 3'
UTR.
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represents the sequence with the longest 5' UTR. The comparison of the
sequences with the genomic sequence (GenBank accession number AL050337)
revealed exons 1–3 of the CRF2-10 gene (Figs. 1
and 2). One of the PCR
products represented a splice variant of the CRF2-10 cDNA, revealing
the existence of an additional exon 4a (Fig. 1, B and
C, and 2). This long splice variant was designated
CRF2-10L. When the fragment of the CRF2-10 cDNA
encoding mature protein was amplified by PCR either from the placental
cDNA library or cDNAs synthesized with total RNA isolated from
LPS-stimulated PBMCs, the existence of another splice variant lacking
exon 5 was revealed (Figs. 1 and 2C). Joining exons 4 and 6
causes a frame-shifting event, resulting in premature termination and,
thus, the generation of a short protein, which was designated
CRF2-10S (Figs. 1 and 2C). Thus, the
entire CRF2-10 gene is composed of 6 exons (Fig. 1). The entire first
exon and a part of the second exon encode the 5' UTR. The rest of the
second exon encodes the signal peptide of the protein. Exons 3–5 and a
portion of exon 6 encode the secreted CRF2-10. The rest of the exon 6
encodes the long 3' UTR with the presence of multiple polyadenylation
signals. In addition, there are alternative splicing events that either
insert the exon 4a between exons 4 and 5, creating a longer CRF2-10
splice variant, or eliminate the exon 5, creating prematurely
terminated short protein (Figs. 1 and 2).
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). Analysis of the DNA segment
demonstrates that the CRF2-10 gene is positioned 
24 kb
apart from the IFNGR1 gene and transcribed in the same
direction as the IFNGR1 gene (Fig. 2). All exon/intron and
intron/exon splice sites conform well to the consensus motifs
(exon/GT-intron-AG/exon).
Comparison of the sequence of the CRF2-10 protein with those of other
members of this family of receptors revealed that CRF2-10 is mostly
homologous to the extracellular domain of the IL-22R1 chain (3, 17, 18) and to the extracellular domain of CRF2-8
(3) (Fig. 2D) The function of CRF2-8 was
recently characterized as a receptor subunit for the IL-20R complex
(26). The comparison reveals that the mature CRF2-10
protein demonstrates 34 and 33% amino acid identity to the
extracellular domains of IL-22R1 and CRF2-8, respectively.
Expression and purification of CRF2-10 and cross-linking
To obtain the CRF2-10 protein, an expression vector was created
encoding FL-CRF2-10. COS-1 cells were transiently transfected with the
expression vector and, 3 days later, conditioned medium containing
FL-CRF2-10 was collected and tested for protein expression. Western
blotting with anti-FLAG Ab revealed that FL-CRF2-10 was produced
and secreted from COS-1 cells (data not shown). FL-CRF2-10 was purified
from conditioned medium by affinity column chromatography and analyzed
by Western blotting with anti-FLAG Ab (Fig. 3A, lane 2). The
purified protein appeared on SDS-PAGE as a broad band in the region of
35–45 kDa, suggesting possible glycosylation of the protein.
Indeed, there are five potential sites for N-linked
glycosylation (Asn-X-Thr/Ser) in CRF2-10. The FL-CRF2-8 protein was
also expressed in COS-1 cells and was purified following similar
protocols and used in experiments as a control (Fig. 3A,
lane 3).
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25–40 kDa (Fig. 3A, lane 4). The
protein can be labeled with [32P]phosphate
(Fig. 3A, lane 5) and cross-linked to the IL-22R
chains expressed on the cell surface (17).
To determine whether CRF2-10 is capable of binding IL-22, cross-linking
experiments were performed in solution. The FL-IL-22-P protein was
labeled, and the 32P-labeled FL-IL-22-P was
incubated with the conditioned medium of COS-1 cells expressing
FL-CRF2-10 (Fig. 3B, lane 8). After 1 h
incubation, bis(sulfosuccinimidyl)suberate was added and cross-linking
was performed. As a control, [32P]FL-IL-22-P
was incubated with the conditioned medium of COS-1 cells transfected
with the empty vector and either left untreated (Fig. 3B,
lane 6) or cross-linked after 1 h of incubation (Fig. 3B, lane 7). In addition,
[32P]FL-IL-22-P was incubated in solution with
either purified FL-CRF2-10 (Fig. 3B, 1 µg, lane
9; 0.1 µg, lane 10) or with purified FL-CRF2-8 (Fig. 3B, 1 µg, lane 11). After a 1-h incubation,
cross-linking was performed, and cross-linked complexes were resolved
on the gel and autoradiographed (Fig. 3B). Radiolabeled
IL-22 migrates as a broad band in the region of 25–40 kDa (Fig. 3, A and B). Cross-linking of the IL-22 in
solution resulted in the appearance of an additional broad band in the
region of 100–140 kDa, likely representing an IL-22 tetramer. In the
presence of the CRF2-10 protein, cross-linking produced an additional
complex migrating as an intense broad band in the region of 55–80 kDa.
Moreover, the intensity of bands corresponding to the IL-22 monomer was
greatly reduced, and cross-linking bands corresponding to the possible
tetramer of IL-22 were depleted, indicating that IL-22 tightly binds
CRF2-10, interfering with the formation of IL-22 oligomers. The pattern
of cross-linking in the presence of the CRF2-8 soluble extracellular
domain in the mixture looks identical with the pattern of complexes
generated by cross-linking of IL-22 to itself (Fig. 3B,
lanes 11 and 7, respectively) indicating the lack
of interaction between CRF2-8 and IL-22.
Biological activity
The functional IL-22R complex is composed of two subunits, the
IL-22R1 chain and the second IL-10R2c chain
(17, 18, 19). Both chains are required for signaling; however,
each chain alone is capable of binding IL-22 (17, 18). The
IL-10R2c chain also plays the role of the second
chain of the IL-10R complex (19). To determine whether
CRF2-10 can neutralize activity of IL-22, we used hamster cells
expressing a chimeric IL-22R complex with the IL-22R1 intracellular
domain replaced with the IFN-R1 intracellular domain
(17). The native receptor complex was modified to
facilitate detection of IL-22-induced biological activities. With this
exchange, IL-22 can activate IFN--like biological responses, such as
MHC class I Ag induction and Stat1 activation, in hamster cells
expressing the chimeric IL-22R1/R1 chain and the intact second
chain, IL-10R2c (17). COS-1
cell-conditioned medium containing IL-22 was left untreated or
incubated with purified FL-CRF2-10 for 1 h. The medium was then
added to the cells expressing the IL-22R1/R1 and
IL-10R2c chains, and the ability of IL-22 to
induce IFN--like biological activities in these cells was tested.
IL-22 up-regulated MHC class I Ag expression in these cells (Fig. 4, thin line, open area)
(17). Incubation of IL-22 with CRF2-10 before addition to
the cells resulted in complete neutralization of the ability of IL-22
to induce MHC class I Ag expression in these cells (Fig. 4, thin line,
shaded area).
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, left panel) (17). Pretreatment for 1 h of
IL-22 with the FL-CRF2-10 protein before addition to the cells
eliminated formation of the IL-22-induced Stat1 DNA-binding complexes
in a dose-dependent manner (Fig. 5, left panel). The
FL-CRF2-8 protein was used as a control and had no effect on IL-22
activity in this assay (Fig. 5, left panel).
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, right panel).
Many cytokines induce the expression of the SOCS genes. In
IL-22-responsive HepG2 human hepatoma cells (27),
the expression of the SOCS-3 gene was induced within 4 h after
treatment with IL-22 (Fig. 6).
IL-22-driven induction of the SOCS-3 gene expression was inhibited by
the addition of CRF2-10 (Fig. 6).
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To further evaluate interaction between IL-22 and CRF2-10, hamster
cells expressing the modified functional IL-22R complex described above
were used for cross-linking. Binding and subsequent cross-linking of
[32P]FL-IL-22-P to the cell surface results in
formation of a number of complexes with molecular masses in the range
between 60 and 240 kDa (Fig. 7, lane 1) (17). These complexes can be competed
out by the addition of an excess of unlabeled IL-22 (Fig. 7, lane
2) (17). In addition, CRF2-10 interferes with binding
of IL-22 to the cells. When [32P]FL-IL-22-P and
CRF2-10 were added to the cells at the same time, the appearance of
cross-linking complexes was greatly reduced (Fig. 7, lane
5). A 1-h incubation of [32P]FL-IL-22-P
with CRF2-10 before addition to the cells almost completely eliminated
the formation of the cross-linked complexes (Fig. 7, lane
3). As in all previous experiments, the presence of the CRF2-8
soluble extracellular domain with
[32P]FL-IL-22-P, whether the proteins were
added to the cells at the same time (Fig. 7, lane 6) or
after a 1-h incubation (Fig. 7, lane 4), did not have any
effect on the cross-linking pattern. Thus, cross-linking experiments
demonstrated that CRF2-10 binds IL-22 and prevents its binding to the
cell surface IL-22R complex.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and 2)
belonging to this family of receptors that was first designated
CRF2-10.
Comparison of the sequence of the CRF2-10 protein with those of other
members of this family of receptors revealed that CRF2-10 is most
homologous to the IL-22R1 chain and to the extracellular domain of
CRF2-8. The function of CRF2-8 was recently characterized as a receptor
subunit for the IL-20R complex (26). However, unlike
IL-22R1 or CRF2-8, CRF2-10 is a soluble secreted protein lacking the
transmembrane and cytoplasmic domains. Based on the homology of CRF2-10
to the IL-22R1 extracellular domain, we hypothesized that it would bind
IL-22 and act as an IL-22 antagonist. Results of several experiments
confirm this hypothesis. By cross-linking, we demonstrated that CRF2-10
binds radiolabeled IL-22 in solution (Fig. 3B). Also, in the
presence of the CRF2-10 protein, IL-22 was unable to interact with the
membrane-bound IL-22R complex (Fig. 7). In addition, CRF2-10
neutralized IL-22 activity. CRF2-10 inhibited the ability of IL-22 to
induce Stat activation in intact IL-22-responsive cells such as A549
human lung carcinoma cells (Fig. 5, right panel). Moreover,
to further evaluate the function of the CRF2-10 protein, we used
IL-22-responsive hamster cells (17). These cells express
the human functional chimeric IL-22R complex composed of the intact
second chain the IL-10R2c and the chimeric
IL-22R1/R1 chain with the IL-22R1 intracellular domain replaced by
the IFN-R1 intracellular domain (17). In these cells,
IL-22 induced Stat1 activation and up-regulated MHC class I Ag
expression (Figs. 4 and 5, left panels), activities
characteristic of IFN- signaling (17). The addition of
CRF2-10 inhibited the ability of IL-22 to induce Stat1 activation and
MHC class I Ag expression in these cells (Figs. 4 and 5, left
panels). We also demonstrated that CRF2-10 inhibited the ability
of IL-22 to induce the expression of SOCS-3 gene in HepG2 human
hepatoma cells (Fig. 6). The results demonstrate that the CRF2-10
protein binds IL-22 and, thus, can be designated the IL-22BP. By
binding IL-22, CRF2-10 blocks the activities of IL-22 (
Figs. 4–6).
Although both chains of the IL-22R complex are required to assemble the
functional receptor, each chain alone is able to bind IL-22 (17, 18). Thus, it is likely that the IL-22 activity can be
negatively regulated by the expression on the cell surface of the
R2c chain unpaired by the IL-22R1 chain. Because
IL-22 binding to the R2c chain expressed alone
does not lead to signaling, it may prevent shedding of IL-22 into the
circulation (local suppression). In addition, the secretion of the
soluble IL-22BP into the circulation can provide systemic inhibition of
IL-22 action. Because incubation of cells expressing the functional
IL-22R complex with IL-22 in the presence of IL-22BP inhibited binding
of IL-22 to the cellular receptors (Fig. 7, lane 5), it
seems likely that IL-22BP has higher affinity for IL-22 binding than
the membrane-bound IL-22R complex. The fact that the complex of IL-22BP
and IL-22, present for 3 days in conditioned medium of cells expressing
modified functional IL-22R complex, was still unable to induce
biological activities (Fig. 4) indicates that the complexes are stable,
and little or no dissociation of the complexes occurs.
IL-22 has been demonstrated to induce production of acute-phase
proteins in liver (27). The production of IL-22BP may be one of the
mechanisms to precisely regulate IL-22 function (Fig. 8). It is interesting to note that all
ESTs for the UniGene Hs.126891 (the CRF2-10 or
IL-22BP gene) were derived from lung tissue, suggesting that
IL-22BP is normally expressed in this tissue and perhaps functions in
local inflamation. It would be of interest to test whether the profile
of the expression of this protein differs between asthmatics and
healthy individuals. The homology between IL-22BP and the IL-22R1
extracellular domain (34% identity) is comparable to that between
IL-22BP and the CRF2-8 extracellular domain (33% identity). It was
recently demonstrated that CRF2-8 is a receptor subunit for IL-20,
which may play a role in psoriasis (26). Thus, it will be
of a great interest to determine whether IL-22BP can bind IL-20 (and/or
other IL-10 homologues) and whether it plays role in psoriasis.
Moreover, although it is unlikely that the short splice variant
(CRF2-10S) would bind IL-22, it is possible that
the long splice variant (CRF2-10L) may still bind
IL-22 and perhaps other IL-10 homologues. It is noteworthy that there
is a mouse EST (GeneBank accession number BB222214) and a bovine EST
(GeneBank accession number BE809214) that encode a mouse and bovine
protein, respectively, homologous to human CRF2-10, indicating that the
CRF2-10 gene is conserved between the species.
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Acknowledgments |
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Footnotes |
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2 The cDNA and deduced amino acid sequences of CRF2-10 and its splice variants were submitted to the GenBank.
3 Address correspondence and reprint requests to Dr. Sergei V. Kotenko or Dr. Sidney Pestka, Department of Molecular Genetics and Microbiology, University of Medicine and Dentistry, Robert Wood Johnson Medical School, Piscataway, NJ 08854. E-mail addresses: kotenkse@umdnj.edu and pestka{at}mbcl.rutgers.edu
4 Current address: Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103.
5 Abbreviations used in this paper: CRF, cytokine receptor family; AcP, accessory protein; IL-22BP, IL-22-binding protein; F, forward; R, reverse; FL, tagged at N terminus with the FLAG epitope; AP, adapter primer; BAC, bacterial artificial chromosome; CRF, cytokine receptor family; EST, expressed sequence tag; UTR, untranslated region; SOCS, suppressors of cytokine signaling; P, phosphorylatable.
Received for publication January 24, 2001. Accepted for publication April 2, 2001.
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References |
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S. Brand, F. Beigel, T. Olszak, K. Zitzmann, S. T. Eichhorst, J.-M. Otte, H. Diepolder, A. Marquardt, W. Jagla, A. Popp, et al. IL-22 is increased in active Crohn's disease and promotes proinflammatory gene expression and intestinal epithelial cell migration Am J Physiol Gastrointest Liver Physiol, April 1, 2006; 290(4): G827 - G838. [Abstract] [Full Text] [PDF]
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K. Boniface, F.-X. Bernard, M. Garcia, A. L. Gurney, J.-C. Lecron, and F. Morel IL-22 Inhibits Epidermal Differentiation and Induces Proinflammatory Gene Expression and Migration of Human Keratinocytes J. Immunol., March 15, 2005; 174(6): 3695 - 3702. [Abstract] [Full Text] [PDF]
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S. J. Levine Mechanisms of Soluble Cytokine Receptor Generation J. Immunol., November 1, 2004; 173(9): 5343 - 5348. [Abstract] [Full Text] [PDF]
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 R. P. Donnelly, F. Sheikh, S. V. Kotenko, and H. Dickensheets The expanded family of class II cytokines that share the IL-10 receptor-2 (IL-10R2) chain J. Leukoc. Biol., August 1, 2004; 76(2): 314 - 321. [Abstract] [Full Text] [PDF]
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 H. A. Whittington, L. Armstrong, K. M. Uppington, and A. B. Millar Interleukin-22: A Potential Immunomodulatory Molecule in the Lung Am. J. Respir. Cell Mol. Biol., August 1, 2004; 31(2): 220 - 226. [Abstract] [Full Text] [PDF]
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 G. Yang, H. Ge, A. Boucher, X. Yu, and C. Li Modulation of Direct Leptin Signaling by Soluble Leptin Receptor Mol. Endocrinol., June 1, 2004; 18(6): 1354 - 1362. [Abstract] [Full Text] [PDF]
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A. Mantovani, M. Locati, N. Polentarutti, A. Vecchi, and C. Garlanda Extracellular and intracellular decoys in the tuning of inflammatory cytokines and Toll-like receptors: the new entry TIR8/SIGIRR J. Leukoc. Biol., May 1, 2004; 75(5): 738 - 742. [Abstract] [Full Text] [PDF]
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T. Peleg-Shulman, L. C. Roisman, G. Zupkovitz, and G. Schreiber Optimizing the Binding Affinity of a Carrier Protein: A CASE STUDY ON THE INTERACTION BETWEEN SOLUBLE ifnar2 AND INTERFERON {beta} J. Biol. Chem., April 23, 2004; 279(17): 18046 - 18053. [Abstract] [Full Text] [PDF]
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F. Sheikh, V. V. Baurin, A. Lewis-Antes, N. K. Shah, S. V. Smirnov, S. Anantha, H. Dickensheets, L. Dumoutier, J.-C. Renauld, A. Zdanov, et al. Cutting Edge: IL-26 Signals through a Novel Receptor Complex Composed of IL-20 Receptor 1 and IL-10 Receptor 2 J. Immunol., February 15, 2004; 172(4): 2006 - 2010. [Abstract] [Full Text] [PDF]
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L. Dumoutier, C. Leemans, D. Lejeune, S. V. Kotenko, and J.-C. Renauld Cutting Edge: STAT Activation By IL-19, IL-20 and mda-7 Through IL-20 Receptor Complexes of Two Types J. Immunol., October 1, 2001; 167(7): 3545 - 3549. [Abstract] [Full Text] [PDF]
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