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Prepublished online as a Blood First Edition Paper on May 13, 2002; DOI 10.1182/blood-2002-01-0015. This Article Abstract Full Text (PDF) All Versions of this Article: 2002-01-0015v1 100/5/1919    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Deng, H. Articles by Sun, R. Search for Related Content PubMed PubMed Citation Articles by Deng, H. Articles by Sun, R. Related Collections Neoplasia Gene Expression Brief Reports Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 September 2002, Vol. 100, No. 5, pp. 1919-1921 BRIEF REPORT Rta of the human herpesvirus 8/Kaposi sarcoma-associated herpesvirus up-regulates human interleukin-6 gene expression Hongyu Deng, Julia T. Chu, Matthew B. Rettig, Otoniel Martinez-Maza, and Ren Sun From the Department of Molecular and Medical Pharmacology and the Department of Medicine, West Los Angeles Veterans Administration Medical Center; the Department of Obstetrics and Gynecology and the Department of Microbiology, Immunology and Molecular Genetics, Jonsson Comprehensive Cancer Center, AIDS Institute; Molecular Biology Institute and Dental Research Institute, University of California at Los Angeles.     Abstract Top Abstract Introduction Study design Results and discussion References Human herpesvirus 8 (HHV-8)/Kaposi sarcoma-associated herpesvirus (KSHV) is linked to a number of malignancies thought to be driven by cytokines, including interleukin-6 (IL-6). Rta, a transcriptional activator encoded by HHV-8/KSHV, activates the viral lytic cycle leading to the expression of several viral genes implicated in viral pathogenesis. However, the effect of HHV-8/KSHV Rta on cellular genes has not been reported. We present evidence that the human IL-6 (hIL-6) gene is up-regulated by Rta. Rta potently activated (up to 164-fold) the hIL-6 promoter in a dose-dependent manner in a transient transfection reporter system. Rta also induced expression of the endogenous hIL-6 gene, as shown by enzyme-linked immunosorbent assays. Activation of the hIL-6 gene by HHV-8/KSHV supports the role of hIL-6 in the development of these malignancies. (Blood. 2002;100:1919-1921) © 2002 by The American Society of Hematology.     Introduction Top Abstract Introduction Study design Results and discussion References Human interleukin-6 (hIL-6) is a multifunctional cytokine, and dysregulation of hIL-6 is implicated in the pathogenesis of several malignancies such as Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD). hIL-6 serves as an autocrine growth factor for cultured AIDS-KS cells and may induce endothelial cell proliferation in KS through a paracrine pathway.1,2 Supernatants from PEL-derived cell lines and PEL effusions contain large quantities of hIL-6.3,4 Anti-hIL-6 neutralizing antibodies delayed PEL tumor progression in SCID mice.5 Overproduction of IL-6 also reproduced some manifestations of MCD in a mouse model.6 Furthermore, anti-hIL-6 or anti-hIL-6 receptor antibodies exerted a therapeutic effect on MCD patients.7,8 Taken together, these data strongly support the involvement of hIL-6 in the pathogenesis of these malignancies. Another common feature of KS, PEL, and MCD is their association with human herpesvirus 8 (HHV-8)/Kaposi sarcoma-associated herpesvirus (KSHV).9-11 HHV-8/KSHV encodes a potent transcriptional activator, Rta, which is necessary and sufficient for initiating viral lytic replication.12,13 Among the lytic genes expressed are homologues of cytokines and chemokines, including viral IL-6 (vIL-6) and viral macrophage inflammatory proteins.14,15 In particular, vIL-6 has been detected in tumor lesions and sera from KS, PEL, and MCD patients and is thought to play an important role in viral pathogenesis.16-18 In addition to pirating cellular genes, it is likely that HHV-8/KSHV has developed strategies to enhance its replication by modulating the regulation of cellular factors. We are investigating the effect of Rta on cellular genes and report here that hIL-6 expression is up-regulated by Rta.     Study design Top Abstract Introduction Study design Results and discussion References Plasmid construction The 1.2-kb hIL-6 promoter region was amplified from total cellular DNA using primers F (5'-GGAAGATCTCTCCTGCAAGAGACACCATCCTGA-3') and R (5'-CGGGAATTCAGGGCAGAATGAGCCTCAGAGACAT3-3'); the underlined nucleotides represent BglII and EcoRI sites, respectively. The PCR fragment was cloned into pSEAP2-basic (Clontech, Palo Alto, CA) to produce phIL6-1200/SEAP. Reporter assays Transfections were performed in 12-well plates using a standard calcium phosphate method for the human embryonic kidney cell line 293T or LipofectAmine PLUS (Invitrogen, Carlsbad, CA) for the immortalized bone marrow stromal cell line R1T.19 At 48 hours after transfection, supernatants and cells were harvested. Supernatants were assayed for secreted alkaline phosphatase (SEAP) activities, using the Great EscAPe SEAP Chemiluminescence Detection Kit (Clontech). Cells were lysed in 1× passive lysis buffer and assayed for Renilla luciferase activities using the Luciferase Reporter Assay System (Promega, Madison, WI). Enzyme-linked immunosorbent assays pcDNA3/Rta12 or pcDNA3 was transfected into 293T or R1T cells in 6-well plates using LipofectAmine PLUS. pcDNA3/Rta contained a 3.1-kb genomic sequence encoding Rta, whose expression was driven by the cytomegalovirus immediate-early promoter/enhancer in the vector. Supernatants from transfected cells were collected at 24, 48, and 72 hours after transfection and were assayed for hIL-6 protein levels using an hIL-6 enzyme-linked immunosorbent assay (ELISA) kit (Biosource International).     Results and discussion Top Abstract Introduction Study design Results and discussion References To investigate the role Rta may play in regulating hIL-6 gene expression, we first examined whether Rta can activate the hIL-6 promoter in a reporter system. A 1200-bp promoter region upstream of the first hIL-6 exon was cloned into the pSEAP2-basic vector to produce phIL6-1200/SEAP. This reporter plasmid was cotransfected into 293T cells with either pcDNA3/Rta (an Rta expression plasmid) or vector alone. To control for transfection efficiency and other experimental variations, pRL-CMV, which constitutively expresses the Renilla luciferase, was included in each transfection. As shown in Figure 1A, phIL6-1200/SEAP was potently activated (164-fold) by Rta. To confirm that activation of the hIL-6 promoter was mediated by the Rta protein, we examined the dose dependence of Rta activation. A fixed amount of the reporter plasmid phIL6-1200/SEAP was cotransfected with increasing amounts of pcDNA3/Rta into 293T cells. As the amount of pcDNA3/Rta in each transfection increased, so did the normalized SEAP activity (Figure 1B), indicating that activation of the hIL-6 promoter by Rta is specific. View larger version (18K): [in this window] [in a new window]   Figure 1. HHV-8/KSHV Rta activates the hIL-6 promoter in a reporter system. (A) Activation of the hIL-6 promoter by Rta in 2 different cell lines. Reporter plasmid phIL6-1200/SEAP (20 ng), pRL-CMV (2 ng), filler DNA (720 ng; plasmid DNA that lacks a mammalian promoter/enhancer), and either pcDNA3/Rta or pcDNA3 (50 ng) were transfected into 293T or R1T cells. Supernatants and cells were harvested at 48 hours after transfection and were assayed for SEAP and Renilla luciferase activities, respectively. SEAP activities from the hIL6 promoter were normalized to the corresponding Renilla luciferase activities. Fold activation by Rta was calculated by comparing the normalized SEAP activity stimulated by Rta to that by pcDNA3. (B) Dose-dependent activation of the hIL-6 promoter by Rta in 293T cells. Cells were transfected with 20 ng phIL6-1200/SEAP, 2 ng pRL-CMV, 720 ng filler DNA, and an increasing amount of pcDNA3/Rta (0-50 ng) and a correspondingly decreasing amount of pcDNA3 (50-0 ng) so that the total amount of pcDNA3 vector backbone remained the same. Reporter activities were assayed at 48 hours after transfection; fold activation by different amounts of pcDNA3/Rta was calculated by comparing the normalized SEAP activities to that stimulated by 0 ng pcDNA3/Rta and 50 ng pcDNA3. These results from the reporter system indicate that Rta activates the hIL-6 promoter in the absence of chromatin structure. We next examined whether Rta also activates the endogenous hIL-6 gene. pcDNA3/Rta or pcDNA3 was transfected into 293T cells, and supernatants were harvested at different time points after transfection. The hIL-6 protein levels in these samples were then assayed by ELISA. Consistent with the lack of endogenous hIL-6 expression in 293T cells, the hIL-6 protein levels were low (less than 7.8 pg/mL, the detection limit of the kit) in pcDNA3-transfected cells (Figure 2A). However, the expression of Rta in 293T cells stimulated hIL-6 expression and resulted in progressively higher amounts of hIL-6 protein accumulating in the supernatant at 48 and 72 hours after transfection (54.0 and 84.5 pg/mL, respectively). View larger version (13K): [in this window] [in a new window]   Figure 2. HHV-8/KSHV Rta activates the endogenous hIL-6 gene. pcDNA3/Rta or pcDNA3 (1 µg) was transfected into 293T (A) or R1T (B) cells. Supernatants were harvested 24, 48, and 72 hours later, diluted where appropriate, and assayed for hIL-6 protein levels by ELISA. Average hIL-6 protein concentrations in the supernatants are indicated by horizontal bars, with the numbers (pg/mL) shown. The detection range of the ELISA kit is 7.8 to 500 pg/mL. Dotted line in panel A indicates the lowest detection limit of the kit. When the hIL-6 level in one or more experiments was lower than 7.8 pg/mL, the average for that time point was not calculated. A logarithmic scale is used in panel B. To further establish the ability of Rta to activate the hIL-6 promoter and to induce hIL-6 protein expression, we performed similar experiments in R1T cells. R1T cells manifest a significant level of basal hIL-6 expression19 and thus complement the use of 293T cells. The reporter plasmid phIL6-1200/SEAP was activated 27-fold by Rta in transient transfection reporter assays in R1T cells (Figure 1A). The fold activation in R1T cells was lower than that in 293T cells because of the higher basal level of the reporter plasmid. Moreover, transfection of pcDNA3/Rta stimulated the expression of endogenous hIL-6 in R1T cells, when compared to transfection of pcDNA3, and resulted in hIL-6 levels of 1209, 5762, and 21 447 pg/mL at 24, 48, and 72 hours after transfection, respectively (Figure 2B). Up-regulation of the hIL-6 gene has emerged as a common theme among herpesvirus infections, and multiple mechanisms may be involved.20-22 In the case of HHV-8/KSHV, latently infected B-cell lines (eg, BC-1 and KS-1) express hIL-6 at high levels.3,4 This is attributed in part to the responsiveness of the hIL-6 promoter to an HHV-8/KSHV-latent gene product, the latency-associated nuclear antigen.19 Because HHV-8/KSHV exists predominantly in a latent state in KS and PEL lesions, the induction of hIL-6 expression by the latency-associated nuclear antigen may play a critical role in the development of these malignancies. Here we have demonstrated that HHV-8/KSHV also stimulates hIL-6 expression through its lytic transcriptional activator, Rta. We hypothesize that activation of hIL-6 by Rta plays an important role in lytic infections. This is especially relevant in patients with HHV-8/KSHV-associated MCD. Our results are consistent with the high plasma hIL-6 levels observed in MCD patients and with the fact that most HHV-8/KSHV-infected cells in MCD lesions express the viral lytic gene expression program driven by Rta.16,17 Interestingly, in a separate study, we demonstrated that Rta also strongly activates the HHV-8/KSHV vIL-6 gene.23 Like hIL-6, vIL-6 promotes the growth of IL-6-dependent B cells and activates signal transduction pathways. However, vIL-6 may stimulate a broader spectrum of target cells because it requires only the ubiquitously expressed gp130 receptor, whereas hIL-6 requires both gp130 and IL-6R for signal transduction.14,15,24 On the other hand, the amount of vIL-6 required to stimulate the growth of IL-6-dependent B cells was greater than that of hIL-6, and the binding affinity of vIL-6 for soluble gp130 was determined to be 1000-fold lower than that of hIL-6/soluble IL-6R complex for gp130.25 Therefore, hIL-6 and vIL-6 may both be important in HHV-8/KSHV replication and pathogenesis, but they may play overlapping yet different roles.     Acknowledgments We thank Mike Johnson and Jiabin An for excellent technical assistance, Dr Tonia Symensma for critical reading of the manuscript, and members of the Sun and Martinez-Maza laboratories for discussion.     Footnotes Submitted January 4, 2002; accepted April 19, 2002. Prepublished online as Blood First Edition Paper, May 13, 2002; DOI 10.1182/blood-2002-01-0015. Supported by National Institutes of Health grants CA91791, CA83525, DE14153, and CA57152, the Jonsson Cancer Center Foundation, the Stop Cancer Foundation, and the Concern Foundation. H.D. is a Lymphoma Research Foundation Fellow. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734. Reprints: Ren Sun, Department of Molecular and Medical Pharmacology, University of California at Los Angeles, Los Angeles, CA 90095-1735; e-mail: rsun{at}mednet.ucla.edu.     References Top Abstract Introduction Study design Results and discussion References 1. Miles SA, Rezai AR, Salazar-Gonzalez JF, et al. AIDS Kaposi sarcoma-derived cells produce and respond to interleukin 6. Proc Natl Acad Sci U S A. 1990;87:4068-4072[Abstract/Free Full Text]. 2. Corbeil J, Evans LA, Vasak E, Cooper DA, Penny R. Culture and properties of cells derived from Kaposi sarcoma. J Immunol. 1991;146:2972-2976[Abstract]. 3. Asou H, Said JW, Yang R, et al. Mechanisms of growth control of Kaposi's sarcoma-associated herpes virus-associated primary effusion lymphoma cells. Blood. 1998;91:2475-2481[Abstract/Free Full Text]. 4. Aoki Y, Yarchoan R, Braun J, Iwamoto A, Tosato G. Viral and cellular cytokines in AIDS-related malignant lymphomatous effusions. Blood. 2000;96:1599-1601[Abstract/Free Full Text]. 5. Foussat A, Wijdenes J, Bouchet L, et al. Human interleukin-6 is in vivo an autocrine growth factor for human herpesvirus-8-infected malignant B lymphocytes. Eur Cytokine Netw. 1999;10:501-508[Medline] [Order article via Infotrieve]. 6. Brandt SJ, Bodine DM, Dunbar CE, Nienhuis AW. Dysregulated interleukin 6 expression produces a syndrome resembling Castleman's disease in mice. J Clin Invest. 1990;86:592-599[Medline] [Order article via Infotrieve]. 7. Beck JT, Hsu SM, Wijdenes J, et al. Brief report: alleviation of systemic manifestations of Castleman's disease by monoclonal anti-interleukin-6 antibody. N Engl J Med. 1994;330:602-605[Free Full Text]. 8. Nishimoto N, Sasai M, Shima Y, et al. Improvement in Castleman's disease by humanized anti-interleukin-6 receptor antibody therapy. Blood. 2000;95:56-61[Abstract/Free Full Text]. 9. Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med. 1995;332:1186-1191[Abstract/Free Full Text]. 10. Chang Y, Cesarman E, Pessin MS, et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science. 1994;266:1865-1869[Abstract/Free Full Text]. 11. Soulier J, Grollet L, Oksenhendler E, et al. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease. Blood. 1995;86:1276-1280[Abstract/Free Full Text]. 12. Sun R, Lin SF, Gradoville L, Yuan Y, Zhu F, Miller G. A viral gene that activates lytic cycle expression of Kaposi's sarcoma-associated herpesvirus. Proc Natl Acad Sci U S A. 1998;95:10866-10871[Abstract/Free Full Text]. 13. Lukac DM, Kirshner JR, Ganem D. Transcriptional activation by the product of open reading frame 50 of Kaposi's sarcoma-associated herpesvirus is required for lytic viral reactivation in B cells. J Virol. 1999;73:9348-9361[Abstract/Free Full Text]. 14. Moore PS, Boshoff C, Weiss RA, Chang Y. Molecular mimicry of human cytokine and cytokine response pathway genes by KSHV. Science. 1996;274:1739-1744[Abstract/Free Full Text]. 15. Nicholas J, Ruvolo VR, Burns WH, et al. Kaposi's sarcoma-associated human herpesvirus-8 encodes homologues of macrophage inflammatory protein-1 and interleukin-6. Nat Med. 1997;3:287-292[CrossRef][Medline] [Order article via Infotrieve]. 16. Staskus KA, Sun R, Miller G, et al. Cellular tropism and viral interleukin-6 expression distinguish human herpesvirus 8 involvement in Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. J Virol. 1999;73:4181-4187[Abstract/Free Full Text]. 17. Parravicini C, Chandran B, Corbellino M, et al. Differential viral protein expression in Kaposi's sarcoma-associated herpesvirus-infected diseases: Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. Am J Pathol. 2000;156:743-749[Abstract/Free Full Text]. 18. Aoki Y, Yarchoan R, Wyvill K, Okamoto S, Little RF, Tosato G. Detection of viral interleukin-6 in Kaposi sarcoma-associated herpesvirus-linked disorders. Blood. 2001;97:2173-2176[Abstract/Free Full Text]. 19. An J, Lichtenstein AK, Brent G, Rettig MB. Kaposi's sarcoma-associated herpesvirus (KSHV) induces cellular interleukin-6 expression: role of the KSHV latency-associated nuclear antigen and AP-1 response element. Blood. 2002;99:649-654[Abstract/Free Full Text]. 20. D'Addario M, Libermann TA, Xu J, Ahmad A, Menezes J. Epstein-Barr virus and its glycoprotein-350 up-regulate IL-6 in human B-lymphocytes via CD21, involving activation of NF-B and different signaling pathways. J Mol Biol. 2001;308:501-514[CrossRef][Medline] [Order article via Infotrieve]. 21. Eliopoulos AG, Stack M, Dawson CW, et al. Epstein-Barr virus-encoded LMP1 and CD40 mediate IL-6 production in epithelial cells via an NF-B pathway involving TNF receptor-associated factors. Oncogene. 1997;14:2899-2916[CrossRef][Medline] [Order article via Infotrieve]. 22. Carlquist JF, Edelman L, Bennion DW, Anderson JL. Cytomegalovirus induction of interleukin-6 in lung fibroblasts occurs independently of active infection and involves a G protein and the transcription factor, NF-B. J Infect Dis. 1999;179:1094-1100[CrossRef][Medline] [Order article via Infotrieve]. 23. Deng H, Song MJ, Chu JT, Sun R. Transcriptional regulation of the interleukin-6 gene of human herpesvirus 8/Kaposi's sarcoma-associated herpesvirus. J Virol. 2002;76:8252-8264[Abstract/Free Full Text]. 24. Molden J, Chang Y, You Y, Moore PS, Goldsmith MA. A Kaposi's sarcoma-associated herpesvirus-encoded cytokine homolog (vIL-6) activates signaling through the shared gp130 receptor subunit. J Biol Chem. 1997;272:19625-19631[Abstract/Free Full Text]. 25. Aoki Y, Narazaki M, Kishimoto T, Tosato G. Receptor engagement by viral interleukin-6 encoded by Kaposi sarcoma-associated herpesvirus. Blood. 2001;98:3042-3049[Abstract/Free Full Text]. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. S. Dela Cruz, S. R. Viswanathan, A. S. El-Guindy, D. Shedd, and G. 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[Abstract] [Full Text] [PDF] This Article Abstract Full Text (PDF) All Versions of this Article: 2002-01-0015v1 100/5/1919    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Deng, H. Articles by Sun, R. Search for Related Content PubMed PubMed Citation Articles by Deng, H. Articles by Sun, R. Related Collections Neoplasia Gene Expression Brief Reports Social Bookmarking                   What's this?

	Copyright © 2002 by American Society of Hematology         Online ISSN: 1528-0020