Ethanol enhances TNF-alpha-inducible NFkappaB activation and HIV-1-LTR transcription in CD4+ Jurkat T lymphocytes.
During the latent phase of human immunodeficiency virus type 1 (HIV-1) infection, CD4+ T cells carrying replication-competent proviral HIV-1 DNA play an important role in persistence of the virus. Several cofactors can induce and or amplify HIV-1 replication and negatively affect disease progression and pathogenesis. Ethanol consumption is an important risk factor for HIV-1 infection, and it has been implicated in increased HIV-1 replication and progression of infection. Because tumor necrosis factor-alpha (TNF-alpha) is an important modulator of HIV-1 replication, in the present study we examined the possible effects of ethanol on TNF-alpha-inducible signaling associated with HIV-1 replication in human CD4+ T cells (Jurkat E6-1). We demonstrate that clinically relevant ethanol concentrations significantly potentiate TNF-alpha-inducible NFkappaB. Although ethanol effectively collaborated with TNF-alpha, by itself it did not have a direct effect on NFkappaB activation. The ethanol-dependent potentiation of TNF-alpha-inducible NFkappaB nuclear translocation was observed to involve the enhanced degradation of IkappaBalpha. Additionally, the ethanol-mediated potentiation of TNF-alpha-inducible NFkappaB activation was abrogated by the known antioxidant pyrrolidinedithiocarbamate, suggesting an important mechanistic role for reactive oxygen species in this process. In correspondence with its effect on NFkappaB, ethanol was also observed to significantly enhance HIV-1 long terminal repeat-dependent transcription induced by TNF-alpha. Overall, the data provide a molecular basis for the possible role of ethanol as a cofactor that can adversely affect HIV-1 infection and pathogenesis.
Dong
Q
Q
Graduate Center for Toxicology, and Department of Internal Medicine, University of Kentucky Medical Center, Lexington 40536-0084, USA.
Kelkar
S
S
Xiao
Y
Y
Joshi-Barve
S
S
McClain
C J
CJ
Barve
S S
SS
D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004357:Drug Synergism; D000431:Ethanol / Q000494:pharmacology*; D016325:HIV Long Terminal Repeat / Q000187:drug effects*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D020672:I-kappa B Proteins; D019169:Jurkat Cells; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; C066229:prolinedithiocarbamate; D000072000:NF-KappaB Inhibitor alpha; D000431:Ethanol; D003513:Cycloheximide; D011392:Proline