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Cutting Edge |
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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; and
Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry, New Jersey Medical School, Newark, NJ 07103.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and DIRS1/IL-20R
(type I
IL-20R). In addition, mda-7 and IL-20, but not IL-19, bind to
another receptor complex, composed by IL-22R and DIRS1/IL20R (type
II IL-20R). In both cases, binding of the ligands results in STAT3
phosphorylation and activation of a minimal promoter
including STAT-binding sites. Taken together, these results demonstrate
that: 1) IL-20 induces STAT activation through IL-20R complexes of two
types; 2) mda-7 and IL-20 redundantly signal through both complexes;
and 3) IL-19 signals only through the type I IL-20R
complex. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The IL10 and MDA7 genes have been mapped on
chromosome 1q31–32, in a region where two additional IL-10-related
genes, IL19 and IL20, also were located. Little
is known about IL-19, except that this gene is expressed by
LPS-activated monocytes (5). The biological activities of
IL-20 have been studied by using transgenic mice overexpressing this
cytokine. These mice are characterized by neonatal lethality with skin
abnormalities, including aberrant epidermal differentiation reminiscent
of psoriasis lesions in human (6). An IL-20R complex was
described as a heterodimer of two orphan class II cytokine receptor
subunits: corticotropin-releasing factor (CRF) 2–8, proposed to be
renamed IL-20R, and DIRS1, designated IL-20R
(6).
In addition to the chromosome 1q31–32 cluster, two other IL-10-related
cytokines, AK155 and IL-22, are located on human chromosome 12q15, near
the IFN-
gene. AK155 is known to be up-regulated by Herpes
saimiri infection of T lymphocytes, but its activity and receptor
remain unknown (7). IL-22 was described originally as an
IL-9-inducible gene and called IL-TIF, for IL-10-related T cell-derived
inducible factor (8). IL-22 activities include induction
of the acute phase response in hepatocytes and are mediated through a
heterodimeric receptor composed of the CRF2–9/IL-22R subunit and the
-chain of IL-10R (9, 10, 11). In addition to its cellular
receptor, IL-22 binds to a secreted member of the class II cytokine
receptor family, which was called IL-22BP, and appears to act as a
natural IL-22 antagonist (12, 13).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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HT-29 intestinal epithelial cells were grown in IMDM medium supplemented with 10% FCS, 0.55 mM L-arginine, 0.24 mM L-asparagine, and 1.25 mM L-glutamine. Human embryonic kidney (HEK) 293-EBV nuclear Ag cells were grown in DMEM medium supplemented with 10% FCS. IL-10 homologs were produced by transient expression in HEK293-EBNA cells by the Lipofectamine 2000 method (Life Technologies, Gent, Belgium). The coding sequences for mda-7, IL-19, and IL-22 were amplified by RT-PCR from RNA of T cells stimulated with anti CD3 Ab. The IL-20 coding sequence was amplified from skin RNA. These cDNAs were cloned into pCEP4 plasmid (Invitrogen, Groningen, the Netherlands) under the control of the CMV promoter. mda-7-Flag, IL-19-flag, IL-20-flag and IL-22-flag were generated from the pCEP4-cytokine constructs by mutating the STOP codon and introducing a sequence encoding a C-terminal flag: Gly-Gly-Gly-Asp-Tyr-Lys-Asp-Asp-Asp-Asp-Lys. The IL-22BP-Ig fusion cDNA was produced as described before (12). For Western blot analysis, 10 µl of HEK293 supernatant was mixed with Laemmli sample buffer and boiled for 5 min before SDS-PAGE and transfer onto a polyvinylidene difluoride membrane (Amersham, Arlington Heights, IL). The membrane was probed with biotinylated anti-flag Ab (25 µg/ml) and with streptavidin-HRP (1/5000; Amersham). An ECL detection kit (Amersham) was used for expression of chemiluminescence. The chemiluminescence signal was detected and quantified with a Kodak (Rochester, NY) Digital Science Image Station 440CF. Anti-phospho-STAT3 Western blots were performed as described previously (8).
The DIRS1/IL-20R cDNA was amplified by RT-PCR from K562 leukemia
cells and cloned into pCEP4 plasmid. The IL-22R cDNA was amplified by
RT-PCR from the HepG2 hepatoma cell line before cloning into the
pEF-BOSpuro expression vector (14). The CRF2–8/IL-20R
cDNA was amplified by PCR from a human placenta cDNA library (Clontech
Laboratories, Palo Alto, CA), and cloned into the pCDEF3 plasmid.
Anti-IL-10R and anti-flag Abs were purchased from Peprotech
(London, U.K.) and from Sigma (Bornem, Belgium), respectively. To
produce anti-hIL-22R Abs, we transfected P815 mastocytoma cells
with the hIL-22R cDNA in the pEF-BOS plasmid before injection into
DBA/2 mice. After rejection of the tumors, the sera of these mice had
high titers of neutralizing anti-hIL-22R Abs and were used at a
1/500 dilution.
Luciferase assays
The cytokine 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 TK
promoter. Transfections of HT29 and HEK293 cells were performed as
follows.
HT-29 cells were electroporated (107 cells in 400
µl, 250 V, 192 
, 1200 µF) with 15 µg of pGRR5 and 15 µg of
each receptor cDNA, separately or in combination. Transfected cells
were seeded in 96-well plates, incubated for 5 h at 37°C, and
then preincubated, or not, for 1 h with anti-IL-22R antiserum
(1/500) or with anti-IL-10R Abs (6 µg/ml). Next, the cells
were stimulated with each cytokine for 2 h. Luciferase activity
was measured with the Luclite plus Assay System kit (Canberra-Packard,
Meriden, CT) with a Top Count microplate scintillation counter
(Canberra-Packard).
HEK293-EBNA cells were seeded in 24-well plates (Nunc, Roskilde,
Denmark) for 24 h. Transfections were conducted by using the
Lipofectamine method (Life Technologies, Gent, Belgium), with 500 ng of
plasmid encoding IL-22R, IL-20R, or IL-20R and with 100 ng of
pGRR5. As an internal control, we used 100 ng of pRL-TK vector
(Promega, Madison, WI) containing the Renilla luciferase
gene under the control of the TK promoter. After 20 h, transfected
cells were stimulated with cytokines, and 2 h later, cells were
pelleted and lysed. Luciferase activity was monitored with the
Dual-Luciferase Reporter Assay System kit (Promega).
IL-22BP interaction assays
Specific interactions between IL-22BP and cytokine-flag fusion proteins were assessed directly or indirectly by ELISA, as follows. Reacti-Bind Maleic Anhydride Activated Polystyrene plates (Pierce, Rockford, IL) were coated overnight at 4°C with 12.5 µg/ml of anti-flag Ab in PBS. The plates were incubated 2 h at 37°C with 50 µl of cytokine-flag fusion proteins (HEK293 supernatants). A total of 10% of supernatant of IL-22BP-Ig was added for 2 h, and bound IL-22BP-Ig was detected by using anti-mouse IgG3 polyclonal Abs coupled to peroxidase (Southern Biotechnology Associates, Birmingham, AL). The enzymatic activity was measured as described previously (12). In the indirect assay, we tested the inhibitory effect of IL-10 homologs on the binding of IL-22BP to IL-22. For this purpose, IL-22BP-Ig (10%) was preincubated with IL-10 homologs 2 h before incubation with Reacti-Bind plates (Pierce) that had been coated with rIL-22 as described previously (12).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To characterize the interactions between IL-10 homologs and
receptors belonging to the class II cytokine receptor family, we
expressed mda-7, IL-19, IL-20, and IL-22 as fusion proteins with a
C-terminal flag sequence by transient transfection of HEK293 cells.
Protein production was checked by Western blot with an Ab specific for
the flag peptide (Fig. 1
A).
HEK293 cells secreted mda-7, IL-19, and IL-22 proteins with a
heterogeneous MW of 23–30 kDa, most likely resulting from
glycosylation. The IL-20-flag protein is secreted as a single band with
a size of 
18 kDa, suggesting that this cytokine is not glycosylated.
Quantification of the chemiluminescence signal indicated that IL-19 and
IL-22 were produced at a similar level, whereas IL-20 and mda-7 were
produced 7-fold less.
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. STAT
activation induced by IL-22 was monitored with the pGRR5 luciferase
reporter (9). As shown in Fig. 1
B
(top left), these cells failed to respond to the
other IL-10 homologs. When HT-29 cells were transfected with the
IL-20R cDNA, both mda-7 and IL-20 induced luciferase production.
Interestingly, this effect was completely blocked by an anti-IL-22R
antiserum, suggesting that mda-7 and IL-20 can activate STAT factors
through a new IL-20R complex composed by IL-22R and IL-20R (Fig. 1B, bottom left).
When cells were transfected with both IL-20R and IL-20R cDNAs,
they became responsive to mda-7, IL-20, and IL-19, and the luciferase
production was not affected anymore by anti-IL-22R Abs (Fig. 1B, bottom right), indicating that this activity
was independent from this chain. Finally, on transfection with the
IL-20R cDNA alone, we failed to detect any response to mda-7, IL-19,
and IL-20 (Fig. 1B, top right), confirming that
IL-20R is required for this process.
To characterize further the different types of receptor complexes, we
used HEK293 cells, which express endogenous IL-10R but not IL-22R.
Untransfected HEK293 cells did not respond to any IL-10 homolog (data
not shown). When the IL-22R cDNA was transfected, only IL-22 induced
luciferase production and STAT-3 phosphorylation (Fig. 2A). Cells transfected with
IL-22R and IL-20R responded not only to IL-22 but also to IL-20 and
mda-7 (Fig. 2B), whereas IL-20R alone did not confer any
cytokine responsiveness (data not shown). Transfection of both
IL-20R and IL-20R cDNAs allowed for STAT activation by mda-7,
IL-19, and IL-20, but not IL-22 (Fig. 2C). No response was
observed in cells transfected with the IL-20R cDNA alone (data not
shown). In all cases, luciferase induction correlated with
phosphorylation of STAT-3, as analyzed by Western
blotting (Fig. 2). Similar results were obtained with HEK293
supernatants containing the wild-type cytokines.
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The observation that two different receptor complexes allowed for
the response to IL-20 and mda-7 raised the possibility that each
complex would respond preferentially to one cytokine. To test this
hypothesis, we analyzed the response of HT-29 cells, transfected either
with IL-20R alone or both IL-20R and IL-20R, to different
dilutions of mda-7, IL-19, and IL-20 supernatants. When both IL-20R
and IL-20R were transfected, mda-7 and IL-20 dilutions showed a
similar dose-response curve, indicating a similar sensitivity to both
cytokines (Fig. 3, bottom).
The activity of IL-19, but not those of mda-7 and IL-20, could be
detected with 0.1% of supernatant, in agreement with the higher
concentration of IL-19 supernatants. When only IL-20R was
transfected, HT-29 cells showed a better response to mda-7 at
nonsaturating dilutions (1% and 0.1% supernatant), indicating that
this type of complex is more sensitive to mda-7 (Fig. 3
top). Similar results were obtained in HEK293 cells (data
not shown).
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cannot substitute for IL-10R in IL-22 signaling
The finding that IL-22R can associate not only with IL-10R as
described previously, but also with IL-20R raised the possibility
that the complex of IL-20R with IL-22R could mediate an IL-22
response. Because IL-10R is ubiquitously expressed, we could not
address this question by direct transfection, but the role of IL-10R
was assessed with an anti-IL-10R Ab. As shown in Fig. 4, this Ab could block the IL-22 activity
both in control HT-29 cells and in cells transfected with the IL-20R
cDNA, indicating that IL-20R cannot substitute for IL-10R when
the latter chain is not accessible to IL-22. The same Ab did not affect
the activity of mda-7 or IL-20 in the same cells (data not shown).
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IL-22BP has been shown to bind IL-22 (12, 13), but
nothing is known concerning its ability to bind other IL-10 homologs.
The fact that this soluble receptor exhibits the same degree of
homology with the extracellular domains of IL-22R and IL-20R
prompted us to test the hypothesis that IL-22BP could also bind IL-20.
In a first set of experiments, we tested the ability of the IL-10
homologs to compete for the binding of IL-22BP to insolubilized IL-22.
Microtiter plates were coated with rIL-22 and incubated with an
IL-22BP-Ig fusion protein in the presence of IL-10 homologs. The
interaction between IL-22 and IL-22BP was detected with an anti-Ig
Ab. As shown in Fig. 5A, only
IL-22 supernatants were able to block IL-22BP binding. To directly
assay the interaction between IL-10 homologs and IL-22BP, we coated
microtiter plates with anti-flag Ab before incubation with
flag-tagged IL-10 homologs. IL-22BP-Ig was added, and interaction was
checked with an anti-Ig Ab. As shown in Fig. 5B, only
IL-22 was able to bind IL-22BP-Ig, and no other IL-10 homolog showed
the same activity.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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c, gp130, and IL-2R. Among the
class II cytokine receptors, the only example of a shared receptor so
far was the IL-10R chain, which is involved in both IL-10 and IL-22
signaling (9, 10, 11). In this paper, we show that IL-22R and
DIRS1/IL-20R are also shared by different receptor complexes. The
IL-20R subunit can associate either with IL-20R, leading to a
functional receptor for IL-19, IL-20, and mda-7 (type I IL-20R
complex). IL-20R also can associate with the IL-22R subunit and lead
to a functional receptor for IL-20 and mda-7, but not for IL-19 (type
II IL-20R complex), as schematically represented in Fig. 6. Additional experiments are needed to
determine which of these chains serve as an actual ligand binding
component or as a Jak-recruiting subunit. Alternatively, these receptor
subunits may be expressed as preassociated complexes at the surface of
the cells.
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Although mda-7 was originally identified several years ago (2), its activities and mode of action remain poorly understood. This protein was reportedly expressed intracellularly and was shown to induce apoptosis in certain tumor cell lines by an unknown mechanism (16, 17). On transfection of the mda-7 cDNA in HEK293 cells, we found most of the protein in the supernatant, indicating that it can be secreted, at least in this cell type. Secretion of the rat and mouse orthologs of mda-7 in various cell types also has been reported (3, 4). Together with our observation that exogenous mda-7 binds to the IL-20R complexes, these data support the hypothesis that mda-7 acts as a paracrine or autocrine factor. However, it remains possible that mda-7 might be expressed either as a cytoplasmic protein, inducing cell growth inhibition and apoptosis, or as a secreted protein acting on various cell types through IL-20R complexes.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Jean-Christophe Renauld, Ludwig Institute for Cancer Research, Avenue Hippocrate, 74, B-1200 Brussels, Belgium. E-mail address: Jean-Christophe.Renauld{at}bru.licr.org
3 Abbreviations used in this paper: mda-7, melanoma differentiation-associated gene 7; CRF, cytokine receptor family; HEK, human embryonic kidney.
Received for publication July 2, 2001. Accepted for publication August 7, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) is a common chain of both the IL-10 and IL-22 (IL-TIF) receptor complexes. J. Biol. Chem. 276:2725.This article has been cited by other articles:
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Y.-C. Liao, W.-G. Liang, F.-W. Chen, J.-H. Hsu, J.-J. Yang, and M.-S. Chang IL-19 Induces Production of IL-6 and TNF-{alpha} and Results in Cell Apoptosis Through TNF-{alpha} J. Immunol., October 15, 2002; 169(8): 4288 - 4297. [Abstract] [Full Text] [PDF]
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D. Lejeune, L. Dumoutier, S. Constantinescu, W. Kruijer, J. J. Schuringa, and J.-C. Renauld Interleukin-22 (IL-22) Activates the JAK/STAT, ERK, JNK, and p38 MAP Kinase Pathways in a Rat Hepatoma Cell Line. PATHWAYS THAT ARE SHARED WITH AND DISTINCT FROM IL-10 J. Biol. Chem., September 6, 2002; 277(37): 33676 - 33682. [Abstract] [Full Text] [PDF]
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K. Ozaki and W. J. Leonard Cytokine and Cytokine Receptor Pleiotropy and Redundancy J. Biol. Chem., August 9, 2002; 277(33): 29355 - 29358. [Full Text] [PDF]
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D. Sarkar, Z.-Z. Su, I. V. Lebedeva, M. Sauane, R. V. Gopalkrishnan, K. Valerie, P. Dent, and P. B. Fisher mda-7 (IL-24) mediates selective apoptosis in human melanoma cells by inducing the coordinated overexpression of the GADD family of genes by means of p38 MAPK PNAS, July 23, 2002; 99(15): 10054 - 10059. [Abstract] [Full Text] [PDF]
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E. G. Caudell, J. B. Mumm, N. Poindexter, S. Ekmekcioglu, A. M. Mhashilkar, X. H. Yang, M. W. Retter, P. Hill, S. Chada, and E. A. Grimm The Protein Product of the Tumor Suppressor Gene, Melanoma Differentiation-Associated Gene 7, Exhibits Immunostimulatory Activity and Is Designated IL-24 J. Immunol., June 15, 2002; 168(12): 6041 - 6046. [Abstract] [Full Text] [PDF]
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K. Wolk, S. Kunz, K. Asadullah, and R. Sabat Cutting Edge: Immune Cells as Sources and Targets of the IL-10 Family Members? J. Immunol., June 1, 2002; 168(11): 5397 - 5402. [Abstract] [Full Text] [PDF]
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A. Pataer, S. A. Vorburger, G. N. Barber, S. Chada, A. M. Mhashilkar, H. Zou-Yang, A. L. Stewart, S. Balachandran, J. A. Roth, K. K. Hunt, et al. Adenoviral Transfer of the Melanoma Differentiation-associated Gene 7 (mda7) Induces Apoptosis of Lung Cancer Cells via Up-Regulation of the Double-Stranded RNA-dependent Protein Kinase (PKR) Cancer Res., April 1, 2002; 62(8): 2239 - 2243. [Abstract] [Full Text] [PDF]
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