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Ludwig Institute for Cancer Research, Brussels, Belgium; and Experimental Medicine Unit, Christian de Duve Institute of Cellular Pathology, Université Catholique de Louvain, Brussels, Belgium
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-9 activities are mediated through a receptor that belongs to the
hemopoietin receptor superfamily and associates with 
c, also
involved in IL-2, IL-4, IL-7, and IL-15 signaling. Upon IL-9
stimulation, the tyrosine kinases JAK3 and JAK1, associated with c
and the IL-9R, respectively, become activated and phosphorylate the
IL-9R on a single tyrosine residue. This amino acid is essential for
activation of transcription factors STAT1, STAT3, and STAT5 by IL-9,
and was shown to be required for most activities of IL-9 investigated
so far, such as cell differentiation, regulation of proliferation, and
inhibition of corticoid-induced apoptosis (9, 10).
To characterize further the biological activities of IL-9, we tried to identify genes inducible by IL-9 by using a cDNA subtraction approach. In this report, using IL-9-stimulated T lymphoma cells, we isolated a new gene encoding a protein with characteristic features of a cytokine: the presence of an N-terminal hydrophobic signal peptide, a predicted size of 20 kDa, and a 22% amino acid identity with IL-10. In addition, the supernatant of cells transiently transfected by this cDNA was found to induce activation of STAT3 and STAT5 in mesangial and neuronal cell lines.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BW5147 lymphoma cells were grown in Iscove-Dulbecco’s medium supplemented with 10% FCS, 50 µM 2-ME, 0.55 mM L-arginine, 0.24 mM L-asparagine, and 1.25 mM L-glutamine. MC9 mast cell line was cultured in the same medium supplemented with mIL-3 (100 U/ml from Chinese hamster ovary (CHO) cell supernatants) or mIL-9 (200 U/ml). MES13 mesangial cells were grown in 3:1 mixture of DMEM medium and Ham’s F12 medium supplemented with 14 mM HEPES, 5% FCS, 50 µM 2-ME, 0.55 mM L-arginine, 0.24 mM L-asparagine, and 1.25 mM L-glutamine. The PC12 rat pheochromocytoma cell line was grown in RPMI 1640 containing 10% FCS. HEK293-EBV nuclear Ag (EBNA)3 human embryonic kidney cells and COS-7 were grown in DMEM medium supplemented with 10% FCS. T helper cell clone TS2 (11) was grown in DMEM medium supplemented with 10% FCS, 50 µM 2-ME, 0.55 mM L-arginine, 0.24 mM L-asparagine, and 1.25 mM L-glutamine, and either mIL-9 (200 U/ml) or hIL-2 (200 U/ml). RAW264.7 cells were cultured in DMEM medium supplemented with 5% FCS (Myoclone Super Plus bovine serum; Life Technologies, Grand Island, NY).
BW5147 cells expressing wild-type or mutated hIL-9R were obtained as previously described (9) and cultured in the presence of 1.5 µg/ml puromycin. Two additional hIL-9R mutants, mut6 (activating STAT1 and -3) and mut7 (activating STAT5), were similarly transfected in BW5147 (10). Recombinant mouse and human IL-9 were produced in the baculovirus system in our laboratory and purified as previously described (12). Human recombinant IL-2 (3.5 x 106 U/mg) was provided by Cetus (Chiron Corporation, Amsterdam, The Netherlands). Human recombinant IL-10 (5 x 105 U/mg) was purchased from Peprotech (London, U.K.)
Representational difference analysis
Total RNA was prepared from BW5147 cells stimulated with mIL-9 (200 U/ml) or normal medium for 48 h, using guanidium isothiocyanate lysis and CsCl gradient centrifugation (13). Polyadenylated RNA was purified from total RNA with oligo(dT) cellulose columns (Pharmacia, Uppsala, Sweden). Double-stranded cDNA was generated from 5 µg poly(A)+ RNA using an oligo(dT) primer and the SuperScript Choice System for cDNA synthesis, according to the manufacturer’s recommendations (Life Technologies). Representational difference analysis was performed as described (14, 15).
After three rounds of subtraction, final difference products were digested with DpnII and cloned into the BamHI site of pTZ19R. Double-stranded plasmid DNA was prepared and sequenced with a Thermo-sequenase Sequencing kit (Amersham, Arlington Heights, IL). Sequence comparisons with the GenBank and EMBL databases were performed with the BLAST search program. Oligo(dT)-primed cDNA libraries generated from IL-9-stimulated BW5147 cells were screened with the mouse IL-10-related T cell-derived inducible factor (IL-TIF) DpnII fragment as described (16).
RT-PCR analysis and Southern blotting
Spleen cells (5 x 106/condition)
from 6-wk-old BALB/c mice were stimulated 24 h in control medium
supplemented or not with LPS (20 µg/ml) or with Con A (1 µg/ml) in
the presence of a blocking anti-mIL-9 goat antiserum (1%). Total
RNA was isolated using the TRIzol Reagent, according to the
manufacturer’s recommendations (Life Technologies). The same method
was used to isolate RNA from cytokine-stimulated cell lines (5 x
106 cells/condition). Protein synthesis inhibitor
cycloheximide (Sigma, St. Louis, MO) was used at 10 µg/ml. Total RNA
was isolated from various organs of 6-wk-old normal FVB/N mice using
guanidium isothiocyanate lysis and CsCl gradient centrifugation
(13). Reverse transcription was performed on 5 µg total
RNA with an oligo(dT) primer. cDNA corresponding to 5 ng of total RNA
was amplified for 35 cycles by PCR with specific primers for IL-TIF as
follows: sense 5'-CTGCCTGCTTCTCATTGCCCT-3' (from position 124 of
the cDNA sequence), antisense 5'-CAAGTCTACCTCTGGTCTCAT-3' (from
position 784 of the cDNA sequence); for ß-actin, sense
5'-ATGGATGACGATATCGCTGC-3', antisense 5'-GCTGGAAGGTGGACAGTGAG-3'
(18 cycles). Annealing temperatures were 57°C and 60°C for IL-TIF
and ß-actin, respectively. The post PCR products were analyzed in
ethidium bromide-stained 1% agarose gels. In some experiments,
specific amplification was confirmed after blotting (
-Probe
membrane, Bio-Rad, Hercules, CA) by hybridization with internal
radioactive probes. The internal probe was
5'-GTCCACGACATCATGCTACTG-3' for ß-actin, and
5'-GACGCAAGCATTTCTCAGAG-3' for IL-TIF.
Transient transfection for production of recombinant IL-TIF protein
For transient transfection of an IL-TIF expression plasmid in
the HEK293-EBNA and COS-7 cell lines, the IL-TIF cDNA was cloned,
respectively, into pCEP-4 plasmid (Invitrogen, Groningen, The
Netherlands) under the control of the CMV promoter and into pEF-BOS
plasmid (17), under the control of the EF-1
promoter.
Cells were seeded in 6-well plates (Nunc, Roskilde, Denmark) at 3
105 cells/well 1 day before transfection.
Transfections were conducted using Lipofectamine method (Life
Technologies), according to the manufacturer’s recommendation 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
IL-TIF. For radioactive labeling of IL-TIF, transfected cells were
incubated in 0.6 ml of methionin-free medium supplemented with 60 µCi
35S-labeled methionin for 24 h, and 12.5
µl of supernatant were analyzed by SDS-PAGE in a 14% acrylamide gel,
followed by autoradiography for 1 day.
Detection of IL-TIF by Western blot analysis
A synthetic peptide beginning with an NH2-terminal cysteine residue followed by the mIL-TIF sequence 40–61 (CKLEVSNFQQPYIVNRTFMLAK) was conjugated to maleimide-activated keyhole limpet hemocyanin (KLH) (inject-maleimide activated carrier proteins; Pierce, Rockford, IL). Two rabbits were immunized with 150 µg of peptide-KLH conjugate in CFA by multiple-site intradermal injection. At 3-wk intervals, the rabbits were boosted with 150 µg of peptide-conjugated in IFA by multisite subcutaneous injections. Fifteen days after the second boost, the animals were test bled.
Ten microliters from supernatant of HEK293 cells transfected with IL-TIF were mixed with Laemmli sample buffer and boiled for 5 min. Proteins were separated on a precast NOVEX SDS-PAGE polyacrylamide gel (14%). After transfer, the polyvinylidene difluoride (PVDF) membrane (Amersham) was blocked in 5% nonfat dry milk, washed, and probed with rabbit polyclonal IL-TIF antiserum (1/500) and with HRP-linked anti-rabbit Ab (1/5000; Amersham). An ECL detection kit (Amersham) was used for expression of chemiluminescence.
STAT activation assays
Nuclear extracts were prepared as described previously
(9). Briefly, cells (5 x 106)
were stimulated for 10 min with transfected 293-EBNA cell supernatants
(1%), washed with PBS, and resuspended in 1 ml ice cold hypotonic
buffer "A" for 15 min (10 mM HEPES buffer (pH 7.5), containing 10
mM KCl, 1 mM MgCl2, 5% glycerol, 0.5 mM EDTA,
0.1 mM EGTA, 0.5 mM DTT, 1 mM Pefabloc (Boehringer Mannheim), 10
µg/ml aprotinin, and 5 mM NaF). The cells were lysed by adding 65
µl Nonidet P-40 10% and vortexing. Nuclei were pelleted (30 s at
14,000 rpm) and extracted for 30 min in 100 µl hypertonic buffer
"B" (buffer "A" supplemented with HEPES (20 mM), glycerol
(20%) and NaCl (420 mM)). Nuclear debris was removed through a 2-min
centrifugation. Analysis of DNA binding activity was performed as
described (18) using a 32P-labeled
oligonucleotide probe corresponding to the 3' 18 bp of the response
region (GRR) of the FcRI gene: upper strand, 5'-ATGTATTTCCCAGAAA-3';
lower strand, 5'-CCTTTTCTGGGAAATAC-3'.
Supershifts were performed by adding the following Abs to the mixture of nuclear extracts and labeled DNA probe: 0.75 µg of anti-STAT1 Ab (catalog no. G16920, Transduction Laboratories, Lexington, KY), 1 µg anti-STAT3 Ab (clone ST3-5G7, Zymed Laboratories, San Francisco, CA), or 1 µg anti-STAT5b Ab (sc no. 835-X, Santa Cruz).
For Western blot analysis, cells (4 x 105) were stimulated for 10 min with 293-EBNA cell supernatants (2%), or with hIL-10 (10 ng/ml), before lysis in 80 µl of SDS sample buffer (Bio-Rad). Five microliters of the samples were separated on a precast NOVEX SDS-PAGE polyacrylamide gel (14%). After transfer, the nitrocellulose membrane (Hybond C, Amersham) was blocked in 5% nonfat dry milk, washed, and probed with rabbit polyclonal anti-phospho-STAT3 Abs (1/10,000, from New England Biolabs, Beverly, MA) and with HRP-linked anti-rabbit Ab (1/5000; Amersham). An ECL detection kit (Amersham) was used for expression of chemiluminescence. The blots were subsequently reprobed with anti-ß actin Abs (1/10,000; from Sigma) to confirm equal loading of the different lanes.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Based on the hypothesis that biological activities of this cytokine result from its ability to activate specific target genes, we performed a representational difference analysis of gene expression on BW5147 lymphoma cells that were stimulated with IL-9 for 24 h. Previously described activities of IL-9 on these cells include protection against dexamethasone-induced apoptosis and induction of differentiation genes such as Granzyme A and Ly6A/E (19). BW5147 cells were stimulated with IL-9 or control medium for 24 h before mRNA extraction. The isolation of IL-9-induced transcripts was performed by using the representational difference analysis technique as described by Hubank and colleagues (14). Oligo(dT)-primed cDNAs were synthesized, digested with DpnII, and used to generate the respective amplicons. After three rounds of subtractive hybridization, the third difference product was cloned, and 24 clones were sequenced. Three different IL-9-induced transcripts were identified. One of these clones consisted of a 225-nucleotide DpnII fragment with no homology with previously described genes. The full-length sequence was obtained by screening of an oligo(dT)-primed cDNA library from IL-9-stimulated BW5147 cells. The largest clone isolated contained 1124 nucleotides including a 537-bp open reading frame that encodes a 179-amino acid protein.
Further analysis of the predicted amino acid sequence showed the
presence of an hydrophobic N-terminal sequence suggestive of a signal
peptide for protein secretion. In addition, protein homology searches
in the GenBank databases with the BlastP program detected a 22% amino
acid identity with mouse and human IL-10. No significant homology was
found with any other cytokine. This protein was designated IL-TIF
(for IL-lo-related T cell-derived Inducible factor ) because
preliminary results from genomic sequencing indicate the existence of
at least another gene encoding a highly related protein. IL-TIFß
differs only from IL-TIF by 3 amino acid changes. The amino acid
alignment of IL-TIF, IL-TIFß, and IL-10 is shown in Fig. 1
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First, the kinetics of IL-TIF expression in BW5147 cells was
studied by RT-PCR after IL-9 stimulation for various periods of time.
RT-PCR was performed with oligonucleotides common to both forms of
IL-TIF. As shown in Fig. 2, IL-TIF mRNA
was up-regulated within 30 min of IL-9 stimulation, and maximal
expression was reached at 3 h of stimulation. This expression was
stable until at least 48 h of IL-9 stimulation. Analysis of IL-TIF
expression in various cell lines revealed that IL-TIF was also induced
in mast cells upon IL-9, but not IL-3 stimulation, as well as in T
helper clones upon IL-9, but not IL-2 stimulation (Fig. 3A). Expression of IL-TIF was
also detected in Con A-activated spleen cells. Noticeably, neutralizing
anti-IL-9 Abs failed to inhibit this induction (Fig. 3B), suggesting either that Con A can directly induce IL-TIF
expression or that other cytokines can also mediate this process.
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). In vivo
expression of IL-TIF was not modified by IL-9 overexpression in
transgenic animals (data not shown), probably resulting from the need
of preactivation to induce IL-9 responsiveness of nontransformed cells
(1).
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To determine whether IL-9 directly up-regulates IL-TIF expression
or whether this process requires protein synthesis, BW5147 cells were
stimulated with IL-9 in the presence of cycloheximide. As shown in Fig. 5, cycloheximide did not affect IL-TIF
expression, as assessed by RT-PCR analysis, indicating that new protein
synthesis is not required for this IL-9 activity. To analyze further
the mechanisms of IL-TIF up-regulation in response to IL-9, we took
advantage of BW5147 transfectant cells expressing mutated forms of the
human IL-9 receptor (hIL-9R). When cells were transfected with the
wild-type hIL-9R, hIL-9 induced a similar IL-TIF expression to that
induced by mIL-9 in the parental cells (Fig. 6). By contrast, hIL-9 was inactive in
cells expressing a mutated form of hIL-9R (phe116) in which tyrosine
residue 116 was replaced by a phenylalanine, resulting in the inability
of the receptor to activate STAT transcription factors. To determine
the respective role of the different STAT proteins activated by IL-9
(STAT1, -3, and -5), other hIL-9R mutants that specifically activate
STAT5 (mut7) or STAT1 and -3 (mut6) were stably transfected in BW5147.
As shown in Fig. 6, STAT5 is not necessary for IL-TIF expression, since
this gene is still induced in BWmut6 cells (where STAT5 is not
activated in response to hIL-9). In addition, STAT5 is not sufficient
for IL-TIF expression, since this gene is not significantly
up-regulated in BWmut7 (where STAT5 is the only STAT activated by
hIL-9).
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Production of recombinant murine IL-TIF protein was performed by
transient transfection of HEK293 cells.
35S-methionin labeling showed that, upon
transfection with the IL-TIF cDNA, HEK293 cells produced a
heterogeneous 23- to 30-kDa protein that was recognized by Abs raised
against an N-terminal peptide of the IL-TIF sequence (Fig. 7). This heterogeneity most likely
results from glycosylation of the protein, which contains four putative
N-linked glycosylation sites.
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, IL-10, but not IL-TIF, strongly
activated STAT3 in these cells. In addition, IL-TIF did not induce the
proliferation of the IL-10 responsive mast cell line MC-9 (data not
shown), indicating that IL-TIF does not activate cells through the
IL-10 receptor.
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RI-derived GAS sequence, which binds to all STAT factors, we
screened a number of in vitro cell lines for the nuclear translocation
of STAT transcription factors after 15 min of IL-TIF stimulation. Using
this assay, we identified two IL-TIF-responsive cell lines: a murine
kidney mesangial cell (MES13) and a rat pheochromocytoma cell (PC12)
(Fig. 9A). Further characterization of
STAT factors that are activated in response to IL-TIF in MES13 cells
was achieved by supershift experiments with Abs specific for STAT-1,
-3, or -5. As shown in Fig. 9B, anti-STAT1 Abs had no
effect on the GRR retardation complex. By contrast, anti-STAT3 Abs
supershifted most of the signal detected, and the weak remaining
complexes were supershifted in by anti-STAT5, indicating that STAT3
and, to a lesser extend, STAT5 are the major STAT transcription factors
activated by IL-TIF in this kidney mesangial cell line.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and
IL-1ß (23% amino acid identity). In addition, most of the identical
residues between IL-TIF and IL-10 are located in the C-terminal half of
the protein, which has been found to be critical for IL-10 activity,
raising the hypothesis that IL-TIF could exert some biological
activities related to those of IL-10. However, HEK293-derived IL-TIF
failed to activate STAT3 in mouse macrophages or to induce the
proliferation of IL-10-responsive MC9 cells, indicating that these
factors do not share the same receptor complex. As previously observed
for IL-10, STAT3 seems to be the main activated STAT protein activated
by IL-TIF. Further analyses of the IL-TIF receptor complex are
definitely needed to assess the extent of redundancy and common
features within IL-TIF and IL-10 signaling. The observation that IL-TIF is expressed in activated T cells and, at a steady state level, in organs such as thymus and brain suggests that this factor exhibits pleiotropic activities, within and outside the immune system. In this respect, the fact that PC12 cells, often used as a model for neuronal cells, respond to IL-TIF stimulation, points to a role for this new cytokine in neurological processes. The other IL-TIF-responsive cell line identified so far was derived from kidney mesangial cells, a cell type that shares several features with macrophages, including the ability to phagocytose, produce inflammatory cytokines, release eicosanoids, and generate inducible NO synthase (20, 21). Considering the important role of IL-10 in regulation of monocyte-macrophage activation, the activity of IL-TIF on this cell type definitely deserves extensive evaluation.
The original goal of this study was to identify genes that mediate the biological activities of IL-9. In vitro, IL-TIF failed to reproduce activities such as induction of proliferation of T helper clones, mast cells, or inhibition of corticoid-induced apoptosis, indicating that these processes are not mediated by autocrine IL-TIF production. In vivo, transgenic mice that overexpress IL-9 do not show enhanced constitutive expression of IL-TIF in the organs tested. However, this possibility still has to be evaluated in various physiopathological situations where a role for IL-9 has been suggested, including asthma (4, 5, 22), and nematode infections (23). The availability of recombinant IL-TIF protein and of Abs against this cytokine should allow to address these questions in the near future.
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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:
3 Abbreviations used in this paper: EBNA, EBV nuclear Ag; IL-TIF, IL-10-related T cell-derived inducible factor; GRR, response region.
Received for publication September 24, 1999. Accepted for publication December 7, 1999.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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