title: Extracellular HIV-1 Tat upregulates TNF-α dependent MCP-1/CCL2 production via activation of ERK1/2 pathway in rat hippocampal slice cultures: inhibition by resveratrol, a polyphenolic phytostilbene.
abstract: Human immunodeficiency virus-1 (HIV-1) associated dementia (HAD) has been attributed to an encephalitis resulting from intense infiltration of monocytes. Evidence suggests that the viral protein Tat, which is released actively from HIV-1 infected cells, can contribute significantly to this process. Therefore, the principal objective of this study was to evaluate the potential molecular basis for the role of extracellular HIV-1 Tat in the induction of monocyte chemotactic protein-1 (MCP-1/CCL2) in the hippocampus, which is primarily linked to cognitive function and most commonly damaged in HAD. We also attempted to identify the mechanism by which resveratrol (trans-3,5,4'-trihydroxystilbene) modulates MCP-1 release in hippocampal tissues exposed to Tat. An ex vivo study using rat hippocampal slices demonstrated a time- and dose-dependent increase in MCP-1 production from Tat-treated hippocampal tissues. This increase was accompanied by the activation of the MEK/ERK pathway and TNF-α production. Tat-induced MCP-1 release was abrogated by inhibitors of tyrosine kinases (TK), herbimycin A or genistein, a finding that supports the MAPK signaling mechanism. The inhibition of the ERK1/2 pathway with SL327 induced a near-complete abolition of the observed Tat-induced effects. Furthermore, anti-TNF-α antibodies suppressed Tat-induced MCP-1 release. Resveratrol, to a level similar to that of SL327, downregulated Tat-induced proinflammatory responses via the inactivation of ERK1/2. These results indicate that the activation of the ERK1/2 pathway and TK are critical factors in the production of TNF-α and MCP-1 in the Tat-exposed hippocampus. Additionally, the inhibition of Tat-induced production of MCP-1 and TNF-α via the inactivation of the ERK1/2 pathway may represent the anti-inflammatory mechanism of resveratrol in the hippocampus.
authors.affiliation: Department of Microbiology, School of Medicine, Ewha Womans University, Yangcheonku, Seoul, Republic of Korea.
authors.forename: Eun Ok
authors.initials: EO
authors.lastname: Lee
authors.forename: Sang Eun
authors.initials: SE
authors.lastname: Kim
authors.forename: Hae Kyung
authors.initials: HK
authors.lastname: Park
authors.forename: Jihee Lee
authors.initials: JL
authors.lastname: Kang
authors.forename: Young Hae
authors.initials: YH
authors.lastname: Chong
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013267:Stilbenes / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D057134:Antibodies, Neutralizing; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D013267:Stilbenes; D014409:Tumor Necrosis Factor-alpha; D054322:tat Gene Products, Human Immunodeficiency Virus; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000077185:Resveratrol