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: Katrina Gee, Jonathan B Angel, Wei Ma, Sasmita Mishra, Niranjala Gajanayaka, Karl Parato, Ashok Kumar
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 281 Issue 42 Pg. 31647-58 (Oct 20 2006) ISSN: 0021-9258 [Print] United States
• PMID: 16920714 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CREB1 protein, human
• Cyclic AMP Response Element-Binding Protein
• DNA Primers
• Enzyme Inhibitors
• Gene Products, tat
• Interleukin-10
• Serine
• Luciferases
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Cyclic AMP Response Element-Binding Protein (metabolism, physiology)
• DNA Primers (chemistry)
• Enzyme Inhibitors (pharmacology)
• Gene Products, tat (chemistry)
• Humans
• Interleukin-10 (metabolism, physiology)
• Luciferases (metabolism)
• MAP Kinase Signaling System
• Mitogen-Activated Protein Kinase 1 (physiology)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Monocytes (metabolism, virology)
• Phosphorylation
• Retroviridae (genetics)
• Serine (chemistry)