Ethanol-mediated regulation of transcription factors in immunocompetent cells.
The immunomodulatory effects of acute and chronic alcohol use are characterized by impaired antigen-specific immune activation and by increased susceptibility to infections due to alterations in innate immune responses and inflammatory mediator production. The central feature of cellular responses to inflammatory and stress signals is the activation of the nuclear regulatory kappa B/Rel family of transcriptional factors via various surface receptor systems in immunocompetent cells. Activation of NF-kappa B, however, is regulated at multiple levels including I-kappa B degradation, nuclear translocation, and by interaction of NF-kappa B/Rel with other transcription factors. Data from our and other laboratories demonstrate that acute alcohol treatment inhibits activation and nuclear binding of the p65/p50 NF-kappa B functional heterodimer in human monocytes, a mechanism likely contributing to inhibition of pro-inflammatory cytokine production. Here we show that acute alcohol-mediated inhibition of NF-kappa B activation in various monocytic cells including human monocytes and murine macrophages. Inhibition of NF-kappa B activation by alcohol in monocytic cells was independent of I-kappa B alpha degradation. These acute-alcohol-induced changes in monocytic cells were different compared to T lymphocytes, both in Jurkat CD4 cells and peripheral human T cells, acute alcohol had a biphasic effect on TNF-alpha-induced NF-kappa B activation via an I-kappa B alpha-dependent mechanism. Inhibition of NF-kappa B activation by acute alcohol in LPS-activated human monocytes was associated with an increase in nuclear glucocorticoid receptor (GR) levels and reduced GR binding to the glucocorticoid response element (GRE). Together these findings support the hypothesis that in the presence of alcohol, nuclear interaction of NF-kappa B (p65) with glucocorticoid receptor and/or other transcription factors may contribute to the reduced NF-kappa B activation. In contrast to the inhibitory effects of acute alcohol on NF-kappa B activation in monocytic cells, chronic alcohol use and alcoholic hepatitis result in an augmentation of NF-kappa B activation and pro-inflammatory cytokine induction. These results suggest that the complex interactions of the NF-kappa B/Rel and related transcription factors including GR and heat-shock responses determine the level of activation of the immunocompetent cells in response to the challenge of acute and chronic alcohol use at the single cell level.
Szabo
Gyongyi
G
Department of Medicine, University of Massachusetts Medical School, LRB 215, 364 Plantation Street, Worcester, MA 01605-2324, USA. gyongyi.szabo@umassmed.edu
Mandrekar
Pranoti
P
D000293:Adolescent; D000328:Adult; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D018869:Heat-Shock Response / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014157:Transcription Factors / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D008070:Lipopolysaccharides; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D003907:Dexamethasone