1 Virologie Humaine INSERM-U412, Ecole Normale Supérieure de Lyon, IFR 128 BioSciences Lyon-Gerland, 46 allée d'Italie, 69364 Lyon Cedex 07, France
2 Biologie Moléculaire de la Différenciation, Université Paris 7 Denis Diderot, 2 place Jussieu, case 7136, 75251 Paris Cedex 05, France
Correspondence
Madeleine Duc Dodon
madeleine.duc.dodon{at}ens-lyon.fr
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ABSTRACT |
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Present address: Department of Biochemistry, University of Cambridge, UK.
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INTRODUCTION |
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Human interleukin 17 (IL17), originally identified as cytolytic T lymphocyte-associated antigen 8 (CTLA-8), displays a significant homology with the T-lymphotropic herpesvirus saimiri gene 13 product (HVS13) (Rouvier et al., 1993; Yao et al., 1995a
). This cytokine is a 2030 kDa homodimeric protein, encoded by a 155 aa open reading frame that includes an N-terminal secretion signal sequence of 1923 residues. IL17 expression is induced only in activated T lymphocytes (predominantly of the CD4+ subtype), cultured either with monoclonal antibodies to CD3 and CD28 molecules or with phorbol myristate acetate (PMA) and Ca2+ ionophore (Fossiez et al., 1996
; Jovanovic et al., 1998
). The human IL17 receptor, identified as a type 1 transmembrane protein, is ubiquitously expressed and has no sequence similarity to any other known cytokine receptors (Moseley et al., 2003
; Yao et al., 1997
). Such a wide distribution explains the broad set of effects induced by IL17. Thus, this cytokine induces the release of cytokines and prostaglandins from different cell types including fibroblasts, endothelial cells, epithelial cells and macrophages (Fossiez et al., 1996
; Jovanovic et al., 1998
). Furthermore, both TNF-
and IFN-
exert a synergistic effect on the IL17-induced secretion of IL6, and the combination of IL17 and TNF-
is effective in promoting granulocyte-macrophage colony-stimulating factor (GM-CSF) release by synovial fibroblasts (Chabaud et al., 2000
; Fossiez et al., 1996
; Yao et al., 1995a
, b
). Consequently, IL17 may be considered as another factor in the cytokine network involved in inflammatory reactions. Finally, IL17 has been linked to numerous inflammatory pathologies, such as rheumatoid arthritis (Kotake et al., 1999
), asthma (Kawaguchi et al., 2001
; Molet et al., 2001
) and lupus (Wong et al., 2001
). Recently, this pro-inflammatory cytokine has been found to promote angiogenesis and tumour growth (Numasaki et al., 2003
), as well as anti-tumour immunity (Benchetrit et al., 2002
).
In the present study, we examined the expression of IL17 by HTLV-1-infected T cells and evaluated the effect of Tax on the transcription of this cytokine gene. We have shown that expression of IL17 mRNA is induced in HTLV-1-infected T cell lines and in T cells expressing Tax. The 5'-flanking region of the human IL17 gene was isolated and the transcription initiation site was determined. We demonstrated that this region contained a functional promoter by transfecting chimeric reporter constructs into HeLa cells. We showed that signals induced by the addition of PMA and Ca2+ ionophore in combination with Tax expression in Jurkat T cells transiently transfected with these plasmids stimulated the activity of the IL17 promoter. Finally, we identified two regions of the promoter fragment through which Tax was able to transactivate the IL17 gene in these activated T cells.
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METHODS |
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Plasmids.
The HTLV-1 Tax expression plasmid pcTax (kindly provided by W. C. Greene) contained the tax sequence under the control of the cytomegalovirus (CMV) promoter. The pCMV plasmid carrying only the CMV promoter was used as the control for all experiments involving the CMV promoter. The M47 and M22 Tax mutant plasmids have been described previously (Smith & Greene, 1990). The LTRCAT reporter construct contained the chloramphenicol acetyl transferase (CAT) sequence under the transcriptional control of the HTLV-I LTR. The pRSV-SEAP construct contained the secreted alkaline phosphatase sequence under the control of the rous sarcoma virus (RSV) promoter (a gift from B. C. Cullen). The pBS-IL17 plasmid was constructed by inserting the 450 bp sequence of IL17 into the EcoRI/BamHI sites of the BlueScript plasmid and was used for the preparation of a riboprobe by an in vitro transcription assay.
RNA extraction, RNase protection assay and amplification by RT-PCR.
RNA extraction was performed after isotonic lysis of the cells in the presence of 0·5 % NP-40 (Chomczynski & Sacchi, 1987). Cytoplasmic RNAs (10 µg) were hybridized for 12 h at 42 °C to 100 000 c.p.m. of the labelled RNA probe prepared by transcription of the antisense sequence of pBS-IL17 by T3 RNA polymerase (Promega) according to the manufacturer's protocol. Hybridization was performed in a 20 µl final volume of hybridization buffer (80 % formamide, 400 mM NaCl, 40 mM Pipes pH 6·4, 1 mM EDTA). The hybridization reactions were diluted with 200 µl digestion buffer containing 15 U RNase I (Promega) for 60 min at 20 °C. Reactions were stopped by the addition of 0·5 % SDS and precipitated in ethanol. The protected RNA fragments were analysed on a 5 % polyacrylamide gel containing 8 M urea and TBE buffer and visualized by autoradiography of the dried gel using an overnight exposure.
For RT-PCR, RNA (2 µg) was first treated with 10 U RNase-free DNase I (Roche Molecular Biochemicals) for 30 min at 20 °C and then for 15 min at 65 °C. This RNA sample was then reverse-transcribed at 42 °C for 1 h in a total volume of 20 µl reaction buffer (50 mM Tris/HCl pH 8·3, 30 mM KCl, 3 mM MgCl2, 10 mM dithiothreitol) containing 50 U expand reverse transcriptase (RT) (Roche Molecular Biochemicals), 100 pmoles oligo(dT)1218 (Sigma) and 20 U RNasin (Promega). A reaction without RT was performed in parallel to serve as a control for the absence of DNA contamination. Five microlitres of the cDNA product was amplified by PCR in a final 50 µl reaction volume containing 20 pmol of gene-specific oligonucleotide primers, 1 mM dNTPs and 2 U mixed thermostable DNA polymerases (Roche Molecular Biochemicals). This mixture was incubated for 3040 cycles at a 55 °C annealing temperature, according to the manufacturer's instructions. The following primers were used: IL17, 5'-ATGACTCCTGGGAAGACCTCATTG-3' (sense) and 5'-TTAGGCCACATGGTGGACAATCGG-3' (antisense), generating a 468 bp fragment; IL6, 5'-TCAATGAGGAGACTTGCCTG-3' (sense) and 5'-GATGAGTTGTCATGTCCTGC-3' (antisense), generating a 260 bp fragment; IL8, 5'-TTGGCAGCCTTCCTGATT-3' (sense) and 5'-AACTTCTCCACAACCCTCTG-3' (antisense), generating a 248 bp fragment; Tax, 5'-TGTTTGGAGACTGTGTACAAGGCG-3' (sense) and 5'-GTTGTATGAGTGATTGGCGGGGTAA-3' (antisense), generating a 237 bp fragment; and -actin, 5'-TGAGCTGCGTGTGGCTCC-3' (sense) and 5'-GGCATGGGGGAGGGCATACC-3' (antisense), generating a 247 bp fragment. Ten microlitres of serial dilutions from each RT-PCR product was analysed by electrophoresis in a non-denaturing 1 % agarose gel containing 0·5 µg ethidium bromide ml1. The gels were then blotted on to a positive nylon membrane (Appligene) for 30 min and hybridized with a 32P-labelled IL17 probe prepared from pBS-IL17 or with an appropriate probe containing the IL6, IL8, tax or
-actin sequence. Labelled DNA products were visualized by autoradiography (Hyperfilm; Amersham). The intensity of signals was monitored by laser densitometry. For each sample, the amount of mRNA was quantified relative to the respective level of
-actin mRNA. Data were obtained utilizing the following formula: relative mRNA=[optical density (OD) cytokine mRNA transcripts of the sample/OD
-actin transcripts of the sample]/[OD cytokine mRNA transcripts of unstimulated cells/OD
-actin transcripts of unstimulated cells].
Real-time quantitative PCRs for IL17 and HTLV-1 Tax/Rex mRNA were performed on a LightCycler System (Roche) using the LightCycler-FastStart DNA Master SYBR Green I kit and the following primers: IL17, 5'-AAACAACGATGACTCCTGGG-3' (sense) and 5'-GAGGACCTTTTGGGATTGGT-3' (antisense); RPX3, 5'-ATCCCGTGGAGACTCCTCAA-3'; and RPX4, 5'-CCAAACACGTAGACTGGGTATCC-3'. The porphobilinogen dehydrogenase (PBGD) gene was amplified as a housekeeping gene to normalize patterns of gene expression using the PBGD primers 5'-GGAATGCATGTATGCTGTGG-3' (sense) and 5'-CAGGTACAGTTGCCCATCC-3' (antisense). In brief, reactions were performed in a 20 µl final volume and contained 1·5 µl FastStart reaction mix SYBR Green I, 4 mM MgCl2, 0·5 µM primers and 2 µl cDNA. The reaction conditions were 95 °C for 8 min, followed by 45 cycles of 10 s at 95 °C, 5 s at 61 °C and 10 s at 72 °C. Calibration curves were derived by running two- to threefold serial dilutions of cDNA obtained from a positive cell line. Cellular cDNA samples were run at several dilutions. Controls included RT RNA samples and water. The threshold cycle values (Ct) were used to plot the calibration curve. Standard curves had a coefficient of variation of at least 0·98. The copy numbers were normalized to the human PBGD values measured in a separate tube. All copy numbers derived were the results of at least two determinations in duplicate.
Isolation of a genomic fragment containing the IL17 5'-flanking region and construction of human IL17 reporter plasmids.
The isolation of the genomic fragment containing the IL17 5'-flanking region was performed by PCR screening of a human P1 library (Genome Systems). The primers used were 5'-CCCGATTGTCCACCATGTGGCC-3' (sense) and 5'-ACCTTCCTTCTTGGAAAGAGGG-3' (antisense). One clone was obtained and subsequently subcloned into the Bluescript vector. Finally, a clone containing a 6·6 kb EcoRI insert with 4·6 kb 5'-flanking sequence and 2 kb of coding and intronic sequences of the human IL17 gene was isolated and sequenced. The 5'-deletion mutants were prepared by insertion of a series of 5'-deletion mutants (from 1043 to 85 fragment) upstream of the bacterial CAT reporter gene in the pBL-CAT plasmid. Sequencing of these mutants was carried out by the dideoxy chain termination method (Sanger et al., 1977) using a Sequenase sequencing kit.
Analysis of the IL17 transcription initiation site by 5' rapid amplification of cDNA ends (RACE).
Mapping of the IL17 transcription initiation site by RACE was performed using a commercial kit (Roche Molecular Biochemicals) according to the manufacturer's instructions. Total mRNAs isolated from human PBLs and from HUT-102 cells by standard techniques were submitted to reverse transcription using a reverse primer (24-mer) located at the end of exon 3 (5'-TTAGGCCACATGGTGGACAATCGG-3'). The 3'-tailed cDNA was submitted to 30 rounds of PCR amplification using an oligo(dT) sense primer and a reverse primer (5'-TGCTGGATGGGGACAGAGTTCAT-3') followed by a nested PCR using a reverse primer located on exon 2 (5'-AGATTCCAAGGTGAGGTGGATCGG-3'). PCR included a denaturation step at 96 °C for 30 s, an annealing step at 55 °C for 30 s and an elongation step at 72 °C for 1 min, after an initial denaturation at 94 °C for 5 min, and was followed by a 10 min elongation. The PCR products were separated by agarose gel electrophoresis, purified and sequenced by the dideoxy chain termination method.
Transfection, CAT and SEAP assays.
HeLa cells seeded at 6x104 cells per well of a 12-well plate were transfected 20 h later, using the Fugene transfection reagent (Roche Molecular Biochemicals) as recommended by the manufacturer. The respective concentrations of plasmid DNA used in each transfection assay (which was performed in triplicate) are given in the relevant figure legends, pRSV-SEAP (40 ng) always being included as an internal control. Two days after transfection, cells were harvested and cell pellets were resuspended in 60 µl lysis buffer (100 mM Tris/HCl pH 7·8, 0·7 % NP-40) and lysed by five repeated freezethaw cycles and analysed for CAT activity. The obtained values were normalized for transfection efficiency related to values of SEAP activity, determined using a chemiluminescent reporter kit (Aurora-NEN).
Transfection of the Jurkat T cells was performed by a DEAEdextran procedure with chloroquine treatment (Grosschedl & Baltimore, 1985). Briefly, the CAT reporter constructs (1·5 µg) were co-transfected into Jurkat cells (2x106 cell) with pcTax (200 ng) or empty vector (pCMV) as control. The transfected cells were divided into aliquots and incubated for 24 h at 37 °C. One aliquot was further treated with 50 ng PMA ml1 (Sigma) and 1 µM Ca2+ ionophore (A23187; Calbiochem) for 6 h. Cells were then harvested and centrifuged. Cell pellets were lysed in 60 µl lysis buffer by five repeated freezethaw cycles. Cell extracts were normalized for protein content using the Bradford technique before assays for CAT activity (Neumann et al., 1987
). CAT results are the mean value of three experiments performed in triplicate±SD.
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RESULTS |
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Transactivation of the IL17 promoter by Tax
To examine the promoter activity of each subregion in the regulatory region, a series of eight 5'-deletion mutants (814, 614, 461, 351, 264, 191, 135 and 85 fused to CAT) was generated from the 1043 bp fragment. Each of these reporter constructs was first co-transfected into HeLa cells in combination, with or without a Tax expression plasmid. In the absence of Tax, the low basal activity observed for each deletion construct was not significantly different from that observed with the pBL-CAT construct (Fig. 4, white boxes). In presence of Tax, the IL17/CAT reporter plasmids spanning from 1043 to 614 and from 351 up to the transcription initiation site were activated approximately 7- to 24-fold by Tax, underlining that these two regions of the IL17 promoter include Tax-responsive elements (Fig. 4
, black boxes). The CAT activity reached a maximum value with the two shortest deletion constructs (135 and 85), delineating a minimal Tax-responsive region upstream of the transcription initiation site. Furthermore, with the 461/CAT construct, a large decrease in CAT activity was observed, underscoring the fact that the 110 bp sequence from 461 to 351 might contain inhibitory elements. Collectively, these data revealed that Tax expressed in HeLa cells activates the transcription of the IL17 gene, through cooperation with transcription factors that bind to specific sites within two regions, one of 153 bp from 614 to 461, the other of 135 bp upstream of the transcription initiation site. Next, the transcriptional activity of the IL17 promoter was evaluated in Jurkat T cells. In the absence of Tax, a weak CAT activity was observed with two of the upstream reporter constructs, 814 and 614 (Fig. 5
A, white boxes). In the presence of Tax, no significant enhancement of the CAT activity could be observed (Fig. 5A
, black boxes). Consequently, we next investigated whether activation of the IL17 promoter by Tax in Jurkat T cells requires the addition of PMA and Ca2+ ionophore. When Jurkat cells transfected with each of the reporter plasmids were then stimulated with PMA and Ca2+ ionophore (in the absence of Tax), a significant increase of CAT activity was observed only with three upstream constructs as well as with the 135 reporter plasmid (Fig. 5B
, white boxes). When Jurkat cells, co-transfected with the Tax vector and the serial deletion constructs, were then stimulated with PMA and Ca2+ ionophore, a 7·5- to 12·5-fold increase in CAT activity was observed with these three upstream constructs (black boxes). The CAT activity, which significantly decreased with the 461 reporter plasmid, increased thereafter to reach a maximal value with the 135 construct. These observations indicated that, in Jurkat T cells, stimulation with both PMA and Ca2+ ionophore together with Tax markedly upregulate IL17 promoter activity. They further showed that the 614 bp fragment of the IL17 5'-flanking region contributes to an efficient transactivation of IL17 gene expression.
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DISCUSSION |
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Nevertheless, based on these results, we consider that the region up to position 614 upstream of the transcription initiation site contains major cis regulatory elements and is therefore needed for an efficient upregulation of the IL17 promoter activity by Tax. Interestingly, the use of Tax mutants that discriminate the activation of gene expression by Tax between the CREB/ATF and the NF-B pathways demonstrated that Tax might activate the IL17 promoter via the former. The presence of several CREB binding sites in the Tax-responsive region of the IL17 promoter pleads for such a possibility.
How is the induction of the IL17 expression by Tax related to the pathology associated with HTLV-1 infection? The link with inflammatory diseases, such as HAM/TSP and arthropathy, may be explained by the pro-inflammatory properties of this cytokine. Despite the fact that expression of IL17 is restricted to activated T cells, expression of the IL17 receptor has been detected in all cells and tissues examined by Northern blot analysis (Fossiez et al., 1996; Yao et al., 1995b
, 1997
). Signalling by the IL17 receptor induces the activation of NF-
B and regulates the activity of extracellular-regulated kinase 1 (ERK1), ERK2, c-jun terminal kinase and p38 mitogen-activated protein kinases (Hsieh et al., 2002
; Shalom-Barak et al., 1998
). Consequently, IL17 has the ability to stimulate the production of other inflammatory cytokines and chemokines, including IL6, IL8, GM-CSF and MCP-1 (Aggarwal & Gurney, 2002
; Fossiez et al., 1996
; Jovanovic et al., 1998
). As mentioned in the Introduction, IL17 is believed to play an important role in the induction and perpetuation of immunopathological processes (Aggarwal & Gurney, 2002
). Indeed, high levels of IL17 are detected in rheumatoid arthritis and in other chronic inflammatory diseases, such as multiple sclerosis and psoriasis. Finally, IL17 has recently emerged as a CD4 T cell-derived cytokine that stimulates the migration of vascular endothelial cells and upregulates elaboration of a variety of pro-angiogenic factors by fibroblasts as well as tumour cells (Numasaki et al., 2003
). Therefore, the biological functions of IL17 deserve further examination to unravel their impact on the course and severity of inflammatory and degenerative HTLV-1-associated diseases.
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ACKNOWLEDGEMENTS |
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Received 19 December 2003;
accepted 2 March 2004.