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Human T-Cell Leukemia Virus Type I Tax Transactivates Human Interleukin 8 Gene Through Acting Concurrently on AP-1 and Nuclear Factor-KB-Like Sites

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Human T-Cell Leukemia Virus Type I Tax Transactivates Human Interleukin 8 Gene Through Acting Concurrently on AP-1 and Nuclear Factor-KB-Like Sites [CANCER RESEARCH 58. 3993-4000. September 1. 1998] Human T-Cell Leukemia Virus Type I Tax Transactivates Human Interleukin 8 Gene through Acting Concurrently on AP-1 and Nuclear Factor-KB-like Sites Naoki Mori,1 Naofumi Mukaida, Dean W. Ballard, Kouji Matsushima, and Naoki Vaniamolo Department of Preventive Medicine and AIDS Research. Research Field of Palhogenesis and Clinical Sciences, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852, Japan ¡N.M.. N. YJ; Department of Pharmacology. Cancer Research Institute, Kanazawa University, Kanayiwa 920, Japan ¡N.M.¡:Department of Molecular Preventive Medicine, School of Medicine. University of Tok\o. Tokyo 113, Japan ¡K.M.I: and Howard Hughes Medical Institute. Vanderhilt University School of Medicine. Nashville, Tennessee 37232-0295 [D. W. BJ ABSTRACT unclear but could be one of the common pathological findings among diseases associated with HTLV-I infection. The transactivator protein, Tax, from the human T-cell leukemia virus IL-8 has potent chemotactic activity for T lymphocytes, as well as type I (HTLV-I) transactivates both viral and cellular genes. Previously, neutrophils (1, 2). Interestingly, T lymphocytes are 10-fold more we had shown that interleukin 8 (II.-8) is constitutively expressed in sensitive to IL-8 than neutrophils in chemotaxis (3). Thus, IL-8 is an HTLV-I-infected cells and in cells transiently expressing Tax. We show here that the II -X promoter is Tax responsive in Jurkat T cells. Further important mediator for tissue infiltration of various subsets of leuko more, using several deletion and mutated plasmids of the 5'-flanking cytes (7). Previously, we and others have shown that IL-8 is consti regulatory region of the ll.-fi gene linked to the luciferase gene as a tutively expressed in HTLV-I-infected T-cell lines and fresh ATL reporter and mutant tax gene expression vectors, we have established that cells (16, 17). These findings raise the possibility that aberrant pro both AP-1 at -126 to -120 and nuclear factor (NF)-KB-like rô-element at duction of IL-8 by leukemic cells in ATL or HTLV-I-infected T cells -80 to —¿71areessential and sufficient for the induction of the IL-8 gene in chronic inflammatory disorders might promote accumulation of T by HTLV-I Tax. In addition, overexpression of the dominant-negative lymphocytes in affected tissues. Yet, the precise mechanism by which mutants of NF-KB inhibitor molecules, In-Hir and Ik-H/i, abolished the HTLV-I induces IL-8 gene expression remains to be defined. Tax-induced activation of IL-8 gene. Gel mobility shift assays detected A possible candidate for the induction of IL-8 gene expression is proteins specifically binding to the AP-1 and NF-KB-like sites in Tax- the tax gene product. HTLV-I regulatory protein Tax is a potent expressing T-cell lines infected with HTLV-I. Similarly, the nuclear trans- transactivator of the HTLV-I long terminal repeat (18, 19) and nu location of proteins specifically bound to these two motifs was shown in JPX-9 cells, a subclone of Jurkat cells, carrying the Tax sequences under merous cellular genes, including IL-2 (20), IL-2Ra (20, 21), IL-la the control of an inducible promoter. Taken together, these results suggest (22), IL-6 (23), IL-10 (24), c-fas (25, 26), and intercellular adhesion that the cooperation of transcription factors NF-KB and AP-1 is essential molecule I (27). Tax does not appear to bind DNA directly (28) but, for transactivation of IL-8 gene by HTLV-I Tax. rather, activates transcription by inducing or modifying the activity of certain host transcription factors, including members of the activating transcription factor/cyclic AMP-responsive element-binding protein INTRODUCTION family, serum responsive factor, AP-1 proteins, and NF-KB (29-32). IL-8,2 a member of the leukocyte chemotactic cytokine (chemo- The KB element is also activated in another manner by Tax. Tax interacts with its inhibitors (plOO. pl05, I«Ba,and IxB-y) and disso kine) family, induces chemotaxis of neutrophils, basophils, and T cells (1-3). Although initially identified in medium from human blood ciates their complexes with NF-KB proteins, inducing the nuclear monocytes stimulated with phorbol myristate acetate or lectins (4, 5), translocation of NF-KB proteins (33-37). Recent studies have dem it was soon realized that many different cell types, including endo- onstrated that Tax induces the phosphorylation and degradation of thelial, epithelial, synovial and T cells, fibroblasts, and some tumor iKBa and I«Bß(38,39). cells have been shown to produce IL-8 (1, 3, 6-8). The production of Previously, we have shown that transient transfection of an expres IL-8 is generally not constitutive but can be induced by a variety of sion vector for Tax led to induction of IL-8 expression at both signals including IL-1, tumor necrosis factor a, endotoxin, lectins, and transcriptional and translational levels in Jurkat T-cell line (16). The phorbol esters in a broad range of cells (1, 2, 4, 7). present study was therefore undertaken to determine the regulatory HTLV-I is the causative agent of ATL, an aggressive and usually elements in the IL-8 promoter that were responsive to Tax. We fatal T-cell malignancy (9, 10). ATL is also characterized by unique demonstrated that the viral transactivator Tax is capable of inducing clinical features such as a remarkable tendency of organ infiltration by the IL-8 promoter in T cells. We determined the regulatory elements leukemic cells into lymph nodes, spleen, liver, lung, and skin (11). in the IL-8 promoter responsive to Tax. HTLV-I infection is also associated with chronic inflammatory dis orders such as tropical spastic paraparesis/HTLV-I-associated mye- MATERIALS AND METHODS lopathy, HTLV-I-arthropathy, and others (12-15). Infiltration of Cell Culture. The human T-cell lines Jurkat, MOLT-4, and the HTLV-I- HTLV-I-infected T cells is also a characteristic commonly found in infected T-cell lines MT-1, HUT-102. C5/MJ. and MT-4 were grown in RPMI these HTLV-I-associated diseases. The mode of prominent tissue 1640 containing lO^r fetal bovine serum. JPX-9 and JPX-9/M (provided by Dr. infiltration of HTLV-I-positive T cells and leukemic cells is still M. Nakamura, Tokyo Medical and Dental University, Tokyo, Japan) are subclones of Jurkat cells, expressing Tax and truncated nonfunctional Tax, Received 2/23/98; accepted 7/1/98. respectively, under the control of the metallothionein promoter (26). The cosls of publication of this article were defrayed in pan by the payment of page Western Blotting. Cellular lysates were fractionated by 10% SDS-PAGE, charges. This article must therefore be hereby marked advertisement in accordance with electrophoretically transferred to polyvinylidine difluoride membranes (Immo- 18 U.S.C. Section 1734 solely to indicate this fact. 1To whom requests for reprints should be addressed, at Department of Preventive bilon-P; Millipore. Bedford, MA) and then analy/.ed for immunoreactivity with a mouse anti-Tax antibody, Lt-4 (provided by Dr. Y. Tanaka, Kitasato Uni Medicine and AIDS Research. Research Field of Pathogenesis and Clinical Sciences. Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto. Nagasaki 852. versity, Kanagawa, Japan; Ref. 40). and horseradish peroxidase-conjugated Japan. Phone: 81-95-849-7846: Fax: 81-95-849-7805. sheep anti-mouse IgG (Amersham Inc., Arlington Heights, IL) with an en 2 The abbreviations used are: IL. interleukin: HTLV-I, human T-cell leukemia virus type I: ATL, adult T-cell leukemia: IL-2Ra, interleukin 2 receptor a; RT-PCR. reverse hanced chemiluminescence detection system (ECL; Amersham, Inc.). transcription-PCR; EMSA. eleclrophoretic mobility shift assay; CRE, cyclic AMP- RT-PCR. Total RNA samples (each l /tg) were converted to single-strand responsive element. cDNA by reverse transcription using the RNA PCR kit (Takara Shuzo, Kyoto. 3993 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1998 American Association for Cancer Research. Tax-INDUCED IL-8 EXPRESSION 1 23456 Site-directed mutagenesis of the IL-8 AP-1, NF-IL-6-like. and «B-likesites was carried out using —¿133-lucplasmid as the wild-type template (46), which converted the AP-1 site TGACTCA (-126 to -120) to TatCTCA, the NF- IL-6-like site CAGTTGCAAATCGT (-94 to -81 ) to agcTTGCAAATCGT. and the icB-like site GGAATTTCCT (-80 to -71 ) to taAcTTTCCT (sites of imitation are indicated in lowercase). «B-luc, WT-luc (provided by Dr. J. Fujisawa. Kansai Medical University. Osaka. Japan), and pCArG-luc (provid ed by Dr. K. Shimotohno, Kyoto University. Kyoto, Japan) are luciferase expression plasmids regulated by five copies of the KB element from the IL-8 ¡L-2Ragene, five copies of the 21-bp viral enhancer (CRE), a monomer of the 302 bp CArG box from the c-fos gene, respectively. Cell Transfection and Luciferase Assays. Transient transfection of cells was performed by electroporation as described previously (22). In all cases, the reference plasmid pRL-CMV, which contains the Renilla luciferase gene under the control of the CMV immediate early enhancer/promoter, was cotransfected to correct for transfection efficiency. Twenty-four h after electroporation, cell lysates were prepared using PicaGene Dual (Toyo Ink Co., Tokyo, Japan). The luciferase activity was normali/ed according to the Renilla luciferase control. Results were confirmed by at least three independent transfections. EMSA. Nuclear extracts were obtained as described (47). Binding reac tions were performed essentially as described previously (22, 24). In some Tax experiments, nuclear extracts were incubated with 100-fold molar excess 203 bp JPX-9 Cd(uM) 0 1 5 10 20 0-actm Tax 548 bp °^ '* B JPX 9 JPX 9/M HTLV-I (-) HTLV-I (4) Cd Fig.
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