title: 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.
abstract: 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 Ser(133) 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 Ser(133) phosphorylation.
authors.affiliation: Department of Pathology, Division of Virology, Research Institute, Children's Hospital of Eastern Ontario, Ottawa K1H 8L1, Canada.
authors.forename: Katrina
authors.initials: K
authors.lastname: Gee
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Angel
authors.forename: Wei
authors.initials: W
authors.lastname: Ma
authors.forename: Sasmita
authors.initials: S
authors.lastname: Mishra
authors.forename: Niranjala
authors.initials: N
authors.lastname: Gajanayaka
authors.forename: Karl
authors.initials: K
authors.lastname: Parato
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
mesh_terms: D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism / Q000502:physiology*; D017931:DNA Primers / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015696:Gene Products, tat / Q000737:chemistry*; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism / Q000502:physiology*; D008156:Luciferases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism* / Q000821:virology; D010766:Phosphorylation; D012190:Retroviridae / Q000235:genetics; D012694:Serine / Q000737:chemistry*
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D017931:DNA Primers; D004791:Enzyme Inhibitors; D015696:Gene Products, tat; D016753:Interleukin-10; D012694:Serine; D008156:Luciferases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3