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

Eun Ok Lee; Sang Eun Kim; Hae Kyung Park; Ji Hee Lee Kang; Young Hae Chong

doi:10.1016/j.expneurol.2011.03.006

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

Eun Ok Lee, Sang Eun Kim, Hae Kyung Park, Ji Hee Lee Kang, Young Hae Chong

Department of Physiology

Research output: Contribution to journal › Article › peer-review

34 Scopus citations

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.

Original language	English
Pages (from-to)	399-408
Number of pages	10
Journal	Experimental Neurology
Volume	229
Issue number	2
DOIs	https://doi.org/10.1016/j.expneurol.2011.03.006
State	Published - Jun 2011

Bibliographical note

Funding Information:
This study was supported by the Korea Research Foundation Grant funded by the Korean Government ( KRF-2008-531-E00019 ), a grant from the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea ( A084504 ), and the National Research Foundation of Korea (NRF) grant funded by the Korea Government (MEST) ( 2010 - 0029353 ).

Keywords

ERK1/2
Hippocampus
HIV-1 Tat
MCP-1
Resveratrol
TK
TNF-α

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.expneurol.2011.03.006

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@article{bc716448c92f4762adc60c3091a19e83,

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.",

keywords = "ERK1/2, Hippocampus, HIV-1 Tat, MCP-1, Resveratrol, TK, TNF-α",

author = "Lee, {Eun Ok} and Kim, {Sang Eun} and Park, {Hae Kyung} and Kang, {Ji Hee Lee} and Chong, {Young Hae}",

note = "Funding Information: This study was supported by the Korea Research Foundation Grant funded by the Korean Government ( KRF-2008-531-E00019 ), a grant from the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea ( A084504 ), and the National Research Foundation of Korea (NRF) grant funded by the Korea Government (MEST) ( 2010 - 0029353 ).",

year = "2011",

month = jun,

doi = "10.1016/j.expneurol.2011.03.006",

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pages = "399--408",

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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. / Lee, Eun Ok; Kim, Sang Eun; Park, Hae Kyung et al.
In: Experimental Neurology, Vol. 229, No. 2, 06.2011, p. 399-408.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Extracellular HIV-1 Tat upregulates TNF-α dependent MCP-1/CCL2 production via activation of ERK1/2 pathway in rat hippocampal slice cultures

T2 - Inhibition by resveratrol, a polyphenolic phytostilbene

AU - Lee, Eun Ok

AU - Kim, Sang Eun

AU - Park, Hae Kyung

AU - Kang, Ji Hee Lee

AU - Chong, Young Hae

N1 - Funding Information: This study was supported by the Korea Research Foundation Grant funded by the Korean Government ( KRF-2008-531-E00019 ), a grant from the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea ( A084504 ), and the National Research Foundation of Korea (NRF) grant funded by the Korea Government (MEST) ( 2010 - 0029353 ).

PY - 2011/6

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N2 - 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.

AB - 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.

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DO - 10.1016/j.expneurol.2011.03.006

M3 - Article

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AN - SCOPUS:79956097572

SN - 0014-4886

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JO - Experimental Neurology

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ER -

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

Bibliographical note

Keywords

UN SDGs

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