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J. Biol. Chem., Vol. 281, Issue 42, 31647-31658, October 20, 2006

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Intracellular HIV-Tat Expression Induces IL-10 Synthesis by the CREB-1 Transcription Factor through Ser¹³³ Phosphorylation and Its Regulation by the ERK1/2 MAPK in Human Monocytic Cells^*

Katrina Gee¹, Jonathan B. Angel^¶2, Wei Ma^¶, Sasmita Mishra^¶3, Niranjala Gajanayaka, Karl Parato, and Ashok Kumar^¶||24

From the Departments of ^||Pathology and Laboratory Medicine and ^¶Biochemistry, Microbiology, and Immunology, Division of Virology and Molecular Immunology, Research Institute, Children's Hospital of Eastern Ontario, Ottawa K1H 8L1 and the Ottawa Health Research Institute and the Division of Infectious Diseases, Department of Medicine, Ottawa Hospital General Campus, University of Ottawa, Ottawa, Ontario K1H 8L6, Canada

Human immunodeficiency virus (HIV)-Tat plays an important role in virus replication and in various aspects of host immune responses, including dysregulation of cytokine production. IL-10, an anti-inflammatory cytokine, is up-regulated during the course of HIV infection representing an important pathway by which HIV may induce immunodeficiency. Here we show that extracellular as well as intracellular Tat induced IL-10 expression in normal human monocytes and promonocytic THP-1 cells. The signaling pathways involved in the regulation of IL-10 production by endogenous Tat remain unknown. To understand the molecular mechanism underlying intracellular Tat-induced IL-10 transcription, we employed a retroviral expression system to investigate the role of MAPKs and the transcription factor(s) involved. Our results suggest that an inhibitor specific for the ERK1/2, PD98059, selectively blocked intracellular Tat-induced IL-10 expression in THP-1 cells. Furthermore, intracellular Tat activated the CREB-1 transcription factor through Ser¹³³ phosphorylation that was regulated by ERK MAPK as determined by IL-10 promoter analysis and gel shift assays. Overall, our results suggest that intracellular HIV-Tat induces IL-10 transcription by ERK MAPK-dependent CREB-1 transcription factor activation through Ser¹³³ phosphorylation.

Received for publication, November 10, 2005 , and in revised form, July 26, 2006.

^* This work was supported in part by grants from the Ontario HIV Treatment Network and the Canadian Institutes of Health Research (to A. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a fellowship from the Ontario HIV Treatment Network.

² Recipient of the Career Scientist Award from the Ontario HIV Treatment Network.

³ Supported by a fellowship from the Ontario Graduate Scholarship program and the Ontario Graduate Scholarships in Science and Technology program.

⁴ To whom correspondence should be addressed: Division of Virology, Dept. of Pathology and Laboratory Medicine, Research Institute, Children's Hospital of Eastern Ontario, 401 Smyth Rd., Ottawa, Ontario K1H 8L1, Canada. Tel.: 613-737-7600 (Ext. 3920); Fax: 613-738-4825; E-mail: address: akumar{at}uottawa.ca.

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