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J. Biol. Chem., Vol. 275, Issue 40, 31335-31339, October 6, 2000
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From the Department of Molecular Biology, Genentech, Inc., South San Francisco, California 94080
Received for publication, June 19, 2000
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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We report the identification of a novel human
cytokine, distantly related to interleukin (IL)-10, which we term
IL-22. IL-22 is produced by activated T cells. IL-22 is a ligand for
CRF2-4, a member of the class II cytokine receptor family. No high
affinity ligand has yet been reported for this receptor, although it
has been reported to serve as a second component in IL-10 signaling. A
new member of the interferon receptor family, which we term IL-22R,
functions as a second component together with CRF2-4 to enable IL-22
signaling. IL-22 does not bind the IL-10R. Cell lines were identified
that respond to IL-22 by activation of STATs 1, 3, and 5, but were
unresponsive to IL-10. In contrast to IL-10, IL-22 does not inhibit the
production of proinflammatory cytokines by monocytes in response to LPS
nor does it impact IL-10 function on monocytes, but it has modest
inhibitory effects on IL-4 production from Th2 T cells.
The class II cytokine receptor
family, also known as the interferon receptor family, includes the
IL-10R,1 tissue factor, the two subunits of the
IFN Materials--
Antibodies used for STAT supershift experiments
were purchased from Santa Cruz Biotechnology. Antibodies for STAT
tyrosine phosphorylation were purchased from Upstate Biotechnology.
Antibodies for isolation of T cells were purchased from Pharmingen.
Recombinant human IL-4, IFN Isolation of IL-22 and Construction of Expression Vectors--
A
cDNA clone encoding IL-22 was identified in the Lifeseq EST data
base (Incyte Pharmaceuticals) and sequenced in its entirety. Coding
sequence for IL-22, IL-10, and the interferon family receptors were
obtained by PCR amplification. Fc fusion proteins (immunoadhesins) were
prepared by fusion of the entire open reading frames of IL-22 and IL-10
in-frame with the Fc region of human IgG1 in the eukaryotic expression vector pRK5tkNEO and the baculovirus vector pHIF, a derivative of pVL1393 purchased from Pharmingen. Fusion proteins were
transiently expressed in human 293 cells or Sf9 insect cells and
purified over a protein A column. IL-22 was also expressed as a
C-terminal 8 × His tag fusion in baculovirus and purified by
nickel affinity column. The identity of the purified protein was
verified by N-terminal sequence analysis. IL-22 was also expressed with
an N-terminal gD epitope tag as described (2). The sequences of the DNA
constructs were confirmed by DNA sequencing.
Gel Shift Assays and Western Blot Analysis--
STAT activation
and supershift assays using the SIE sequence and Western blot analysis
of STAT tyrosine phosphorylation were performed as described previously
(3) and as recommended by antibody suppliers.
Isolation of Monocytes and T Cells--
Monocytes were enriched
from fresh human blood by isolation of leukocytes using Lymphocyte
Separation Medium purchased from ICN Biomedicals followed by enrichment
of monocytes by adherence to tissue culture flask. Monocytes were then
cultured for 24 h in 10% fetal bovine serum RPMI medium plus
indicated cytokine treatment. For IL-22 mRNA expression
experiments, resting T cells were isolated from leukocytes by negative
selection with antibodies to CD14, CD19, CD56, CD11A, and HLA-DR
purchased from Pharmingen. Isolated T cells were cultured in 10% fetal
bovine serum RPMI medium with anti-CD3 coated plates for 48 h with
concanavalin A (2.5 µg/ml). To drive T cell differentiation to Th1
and Th2 T cells, CD4 positive cells were first isolated with anti-CD4 magnetic beads (Pharmingen). Cells were then cultured RPMI with an
equal number (~10 million) of irradiated monocytes in the presence of
concanavalin A (2.5 µg/ml) and IL-2 (4 ng/ml) and either IL-12 (8 ng/ml) + anti IL-4 (0.5 µg/ml) or IL-4 (4 ng/ml) + anti-IFN As part of a larger effort to identify novel secreted proteins, we
identified a novel human sequence that bears significant similarity to
IL-10 (Fig. 1A). This protein
also strongly resembles a recently identified murine protein termed
IL-TIF
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
receptor, the two subunits of the IFN
/
receptor, and
CRF2-4. Additional members of this family also exist in human genomic
sequence (1).2 The known
biological actions mediated by these molecules are diverse and include
the antiviral actions of IFN, IFN, and IFN, the
immunomodulatory effects of IFN, a TH1 cytokine that potentiates inflammatory responses and promotes cell-mediated immune responses, the
multiple and generally immunosuppressive actions of IL-10, and the role
of tissue factor as a high affinity receptor for plasma factor VII/VIIa
involved in cellular initiation of the coagulation cascade. The class
II cytokine receptors are evolutionarily related and are characterized
by the presence of a single transmembrane domain and an extracellular
domain that contains several fibronectin-type three repeats. Given the
great importance of members of the interferon receptor family, it is of
interest to identify proteins that interact with this system as they
are likely to perform significant immune functions. In this report we
identify a new human cytokine, IL-22, that signals through a receptor
complex that contains CRF2-4 and a new member of the class II cytokine
receptor family. CRF2-4 has previously been demonstrated to be a
functional component of the IL-10 signaling complex. This is the first
example within the class II cytokine receptor family of a receptor
being utilized as a component of multiple distinct cytokine signaling complexes.
EXPERIMENTAL PROCEDURES
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
, IL-10, and IL-12 was purchased from R&D
Systems. Human TNF, IL-1, IL-4, IL-6, IL-13, and IFN enzyme-linked
immunosorbent assay were purchased from R&D Systems.
(0.6 µg/ml) for Th1 or Th2, respectively. After 3 days, T cells were
collected and washed twice and cultured for 24 h in the presence or absence of IL-22-His (8 nM).
RESULTS
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
, and is likely its human ortholog. Based on its similarity to
the cytokine IL-10 and the data presented herein on the identification
of its receptor as a member of an established cytokine receptor family
and its production within leukocytes and action upon leukocytes, this molecule may appropriately be considered an interleukin. Following convention, we propose terming this molecule human IL-22. The isolated
cDNA encodes a protein of 179 amino acids that is 23% similar to
IL-10 and 78% identical to IL-TIF (4). The first 33 amino acids are
predicted to function as a signal sequence. N-terminal amino acid
analysis of IL-22 expressed and purified using baculovirus confirm the
mature sequence begins at amino acid residue 34. Northern expression
analysis showed only trace level expression in several peripheral
tissues (not shown). RT-PCR analysis showed that IL-22 mRNA is
up-regulated in T cells stimulated with anti-CD3 and further induced by
exposure to concanavalin A (Fig. 1B).
View larger version (28K):
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Fig. 1.
Sequence and expression of IL-22.
A, sequence of human IL-22. The predicted amino acid
sequence is shown. Potential glycosylation sites are boxed.
The four cysteines conserved with IL-10 are highlighted with
bullets, and the signal sequence is underlined.
B, induction of IL-22 mRNA in T cells was detected by
RT-PCR. T cells were cultured for 48 h without treatment
(lane 1) with anti-CD3-coated plates (lane 2) or
with anti-CD3-coated plates plus concanavalin A (1 µg/ml) (lane
3). Total mRNA (50 ng) from T cells was reverse transcribed
and analyzed for the presence of IL-22 by amplification of the cDNA
with a primer pair corresponding to the open reading frame. PCR
products were resolved by agarose electrophoresis, transferred to nylon
membrane, and probed with full-length cDNA probe.
To establish whether IL-22 was ligand for any of the members of the
class II cytokine receptors, each receptor was tested for its ability
to bind IL-22. Cells transiently expressing CRF2-4 showed strong
binding of IL-22-fc fusion protein (immunoadhesion) (Fig.
2A). In contrast, IL-10-fc
bound only to IL-10R. IL-22 also displayed low but detectable binding
to a new member of the family of unknown function which we identified
by searching sequences present in public sequence databases (1), which
we term IL-22R (Fig. 2B). IL-22R is a 574-amino acid protein
most related to IL-10R and CRF2-4 (Fig. 2C). To confirm the
direct interaction of IL-22 with CRF2-4 and IL-22R, binding studies
were conducted with epitope-tagged ligand and soluble receptor
immunoadhesins. IL-22 bound to CRF2-4 but not to any of the other
members of the interferon receptor family (Fig. 2D). Direct
binding was not observed by Western blot analysis with IL-22R,
suggesting the interaction with this component may be of low
affinity.
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Reasoning that IL-22 likely activated the JAK-STAT signaling pathway in
a manner analogous to that observed with the interferons and members of
the hematopoietic cytokine family, we surveyed a series of cell lines
for activation of STAT transcription factors in response to IL-22. Two
cell lines were observed to show rapid and robust STAT activation;
TK-10, a renal cell carcinoma (Fig. 3A) and SW480, a colon
adenocarcinoma (not shown). TK-10 did not induce STAT activity in
response to IL-10. Interestingly, in this survey we observed another
cell line, MOLT-4, a human lymphoblast cell line that did respond to
IL-10 but did not respond to IL-22. The specific STAT proteins
activated in response to IL-22 were examined using antibodies to the
known STATs. In gel-shift assays, antibodies to STAT1, STAT3, and STAT5
were able to supershift IL-22 induced binding complexes to an SIE
sequence (Fig. 3B) and other related STAT-binding elements
(not shown). Furthermore, using antibodies specific for
tyrosine-phosphorylated STAT, clear tyrosine phosphorylation of these
STATs was observed in response to IL-22 (Fig. 3C).
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As IL-22 and IL-10 signal STAT activation in distinct cell lines, we
explored the expression pattern of IL-10R, CRF2-4, and IL-22R in these
lines. RT-PCR analysis indicated CRF2-4 is expressed in both TK-10 and
MOLT-4 (Fig. 4A). In contrast,
expression of IL-10R was detected in MOLT-4 and not in TK-10 and IL-22R
expression was detected in TK-10 but not MOLT-4. These results
suggested that functional signaling complexes for IL-10 included IL-10R and CRF2-4 as previously reported, and that IL-22 signaled through a
complex that included CRF2-4 and IL-22R. To test this hypothesis, these receptors were transfected into COS cells and the ability of
IL-10 and IL-22 to mediate STAT activation was determined (Fig. 4B). In agreement with previous reports IL-10 was able to
mediate STAT activation in cells transfected with both CRF2-4 and
IL-10R. Somewhat weaker activation was also seen in cells transfected with IL-10R alone. In contrast, IL-22 was able to mediate STAT activation in cells transfected with both CRF2-4 and IL-22R but not
with either receptor transfected alone.
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Given the distant homology between IL-22 and IL-10, we examined whether
IL-22 had similar biological activities to IL-10. Monocytes from
freshly isolated human blood were examined for the ability of IL-22 to
effect production of cytokines known to be regulated by IL-10. LPS
induces a large increase in TNF production, an effect which may be
substantially repressed by the presence of IL-10 (Fig.
5). We observed that IL-22 had little if
any effect on TNF production in the presence or absence of LPS.
Furthermore, at 10-fold molar excess IL-10, it did not appear to
inhibit the action of IL-10. Similar results were observed measuring
production of IL-1 and IL-6 (not shown). The effect of IL-22 on
production of cytokines by T cells was studied. Human T cells were
polarized in vitro to either Th1 or Th2
differentiation by activation with concanavalin A in the presence of
IL-12 and anti-IL-4 antibodies or IL-4 and anti-IFN antibodies,
respectively. Cells were then washed and cultured in the presence or
absence of IL-22 for 24 h. IL-22 treatment had little effect on
IFN production from Th1 cells, but modestly inhibited
production of IL-4 from Th2 cells (Table
I).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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IL-22 signals through a receptor complex that includes CRF2-4 and
a new member of the class II cytokine receptor family, IL-22R. Previous
reports have demonstrated that CRF2-4 serves as a second component in
IL-10 signaling (5, 6). CRF2-4 was initially discovered and identified
as a member of the interferon receptor family on the basis of sequence
similarity (7, 8). The gene is located within a cluster that also
includes IFN-R1, IFN-R2, and IFN-R2 on human chromosome 21. A
two-component receptor for IL-10 signaling parallels the IFN/ and
IFN systems which have each been shown to signal through two
component receptors. The data presented here suggest that, in addition,
CFR2-4 serves as a binding component of an IL-22 signaling complex.
Thus CRF2-4 could serve in combination with IL-10R to transduce IL-10
signaling and also function within a signaling complex for IL-22 that
likely includes the new member of this family, IL-22R. Overexpression of CRF2-4 alone or in combination with IL-10R does not appear to be
sufficient to enable IL-22-dependent STAT activation, but combined with IL-22R does enable STAT activation. While shared receptor
components have not been previously observed among the class II
cytokine receptor family, within the large family of hematopoietic
cytokine receptors such utilization of receptors in multiple distinct
combinations to respond to different cytokines is common. Examples
include the common -chain utilized by IL-3, IL-5, and GM-CSF, the
common -chain utilized by IL-2, -4, -7, -9, and -15, and gp130
utilized by multiple members of the IL-6 family of cytokines (reviewed
in Refs. 9-11). The LIF receptor serves both as a ligand binding
subunit for LIF and CT-1 and also as a second component in signaling
complexes for oncostatin M and ciliary neurotrophic factor (12,
13). In each of these cases the ligands, as in the case of IL-10 and
IL-22, are evolutionarily related.
Activation of STATs 1, 3, and 5 has also been reported for both IL-10
and murine IL-TIF (4, 14, 15). These same STATs have also been shown
to be activated by a great number of hematopoietic cytokines,
suggesting that other considerations such as the pattern of receptor
expression influence the biological responses (reviewed in Ref.
16).
Mice with targeted disruption of either CRF2-4 and IL-10 have been
reported (6, 17, 18). The phenotypes bear some similarity but also
significant differences. Mice deficient in IL-10 developed chronic
enterocolitis, were anemic, and were growth retarded when raised in a
conventional environment. In comparison only 60% of the CRF2-4 mice
raised under similar conditions had colitus but this was limited to the
large intestine and did not involve the small intestine. The mice did
not develop anemia and unlike the IL-10-deficient mice the CRF2-4 mice
displayed a 4-fold increase in spleen to body weight with
extramedullary hematopoiesis in the spleen of erythroid, myeloid, and
megakaryocytic lineages. These differences may be due in part to
contributions of environment or genetic background, however, in light
of the existence of a specific ligand for CRF2-4, the function of
IL-10 in the CRF2-4-deficient mice should be re-evaluated. The broad
distribution of CRF2-4 expression is reminiscent of the expression
patterns seen for the receptors for IFN/ and IFN whereas the
expression of the IL-10R is restricted mainly to hematopoietic cells.
Preliminary data suggests IL-22R is also restricted in its expression,
but is detectable by RT-PCR in CD3 positive T cells and at low levels in several peripheral tissues (not shown). The broad expression of
CRF2-4 may reflect the existence of additional ligands yet to be
discovered which also share CRF2-4 as a common subunit. Interestingly,
IL-10 and IL-22 appear to have somewhat mirror actions acting to
promote Th2 or Th1 type responses, respectively. The ability of IL-22
to suppress IL-4 production may have therapeutic potential,
particularly in the treatment of asthma.
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ACKNOWLEDGEMENTS |
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We thank Diane Pennica, Sherman Fong, and Paul Godowski for helpful discussions and Amy Carlow, Jeffrey Hooly, Peter Ng, and Mark Vasser for technical assistance.
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FOOTNOTES |
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* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF279437 and AF286095.
To whom correspondence should be addressed. Tel.: 650-225-8996;
Fax: 650-225-6497; E-mail: nico@gene.com.
Published, JBC Papers in Press, June 29, 2000, DOI 10.1074/jbc.M005304200
2 M-H. Xie, S. Aggarwal, W-H. Ho, J. Foster, Z. Zhang, J. Stinson, W. I. Wook, A. D. Goddard and A. L. Gurney, unpublished observations.
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ABBREVIATIONS |
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The abbreviations used are: IL, interleukin; IFN, interferon; STAT, signal transducers and activators of transcription; RT-PCR, reverse transcriptase-polymerase chain reaction.
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REFERENCES |
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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