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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

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
Authors
Lee E.O.Kim S.E.Park H.K.Kang J.L.Chong Y.H.
Ewha Authors
박혜경이지희정영해
SCOPUS Author ID
박혜경scopus; 이지희scopus; 정영해scopus
Issue Date
2011
Journal Title
Experimental Neurology
ISSN
0014-4886JCR Link
Citation
vol. 229, no. 2, pp. 399 - 408
Indexed
SCI; SCIE; SCOPUS WOS scopus
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. © 2011 Elsevier Inc.
DOI
10.1016/j.expneurol.2011.03.006
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의학전문대학원 > 의학과 > Journal papers
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