Article

Acute alcohol inhibits the induction of nuclear regulatory factor kappa B activation through CD14/toll-like receptor 4, interleukin-1, and tumor necrosis factor receptors: a common mechanism independent of inhibitory kappa B alpha degradation?

University of Massachusetts Medical School, Department of Medicine, Worcester 01605-2324, USA.
Alcoholism Clinical and Experimental Research (Impact Factor: 3.31). 12/2002; 26(11):1609-14. DOI: 10.1097/01.ALC.0000036926.46632.57
Source: PubMed

ABSTRACT Nuclear translocation and DNA binding of the nuclear factor kappaB (NF-kappaB) is an early event in inflammatory cell activation in response to stimulation with bacterial components or cytokines. Cell activation via different receptors culminates in a common pathway leading to NF-kappaB activation and proinflammatory cytokine induction. We have previously shown that acute alcohol inhibits NF-kappaB activation by lipopolysaccharide (LPS) in human monocytes. Here we investigated whether acute alcohol treatment of human monocytes also inhibits NF-kappaB when induced through activation of the interleukin (IL)-1 or tumor necrosis factor (TNF) receptors.
Human peripheral blood monocytes were treated with LPS, TNFalpha, and IL-1beta in the presence or absence of 25mM alcohol for 1 hr. NF-kappaB activation was determined by electrophoretic mobility shift assays using nuclear extracts. Inhibitory kappaB(alpha) (IkappaB(alpha)) was estimated by Western blotting in cytoplasmic extracts. Chinese hamster ovary cells expressing human CD14 were treated with LPS in the presence or absence of alcohol to study NF-kappaB and IkappaB(alpha) regulation.
Our results indicate that acute alcohol inhibits IL-1beta- and TNFalpha-induced NF-kappaB activation. We further show in CD14/toll-like receptor 4-expressing Chinese hamster ovary cells the specificity of alcohol-mediated inhibition of NF-kappaB via the toll-like receptor 4/CD14 receptors. Inhibition of NF-kappaB by acute alcohol was concomitant with decreased levels of the IkappaB(alpha) molecule in the cytoplasm of LPS, IL-1, and TNFalpha-activated monocytes.
These data suggest a unique, IkappaB(alpha)-independent pathway for the inhibition of NF-kappaB activation by acute alcohol in monocytes. Universal inhibition of NF-kappaB by acute alcohol via these various receptor systems suggests a target for the effects of alcohol in the NF-kappaB activation cascade that is downstream from IkappaB(alpha) degradation. Further, these results demonstrate that acute alcohol is a potent inhibitor of NF-kappaB activation by mediators of early (LPS) or late (IL-1, TNF(alpha)) stages of inflammation in monocytes.

0 Followers
 · 
24 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Moderate alcohol consumption has various effects on immune and inflammatory processes, which could accumulatively modulate chronic disease risk. So far, no comprehensive, integrative profiling has been performed to investigate the effects of longer-term alcohol consumption. Therefore, we studied the effects of alcohol consumption on gene expression patterns using large-scale profiling of whole-genome transcriptomics in blood cells and on a number of proteins in blood. In a randomised, open-label, cross-over trial, twenty-four young, normal-weight men consumed 100 ml vodka (30 g alcohol) with 200 ml orange juice or only orange juice daily during dinner for 4 weeks. After each period, blood was sampled for measuring gene expression and selected proteins. Pathway analysis of 345 down-regulated and 455 up-regulated genes revealed effects of alcohol consumption on various signalling responses, immune processes and lipid metabolism. Among the signalling processes, the most prominently changed was glucocorticoid receptor signalling. A network on immune response showed a down-regulated NF-κB gene expression together with increased plasma adiponectin and decreased pro-inflammatory IL-1 receptor antagonist and IL-18, and acute-phase proteins ferritin and α1-antitrypsin concentrations (all P < 0.05) after alcohol consumption. Furthermore, a network of gene expression changes related to lipid metabolism was observed, with a central role for PPARα which was supported by increased HDL-cholesterol and several apo concentrations (all P < 0.05) after alcohol consumption. In conclusion, an integrated approach of profiling both genes and proteins in blood showed that 4 weeks of moderate alcohol consumption altered immune responses and lipid metabolism.
    The British journal of nutrition 12/2011; 108(4):620-7. DOI:10.1017/S0007114511005988 · 3.34 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Aims: To evaluate the effect of acute and chronic consumption of red wine or de-alcoholized red wine with a similar antioxidant capacity on plasma total antioxidant capacity (TEAC), nuclear factor-κB (NF-κB) activity and F2-isoprostanes (8-iso-PGF(2α)) in healthy men. Methods: Nineteen healthy men with an increased waist circumference (≥94 cm) and a body mass index above 25 kg/m(2) participated in a randomized, controlled crossover design trial. They daily consumed 450 ml of red wine (four drinks; 41.4 g alcohol) or 450 ml of de-alcoholized red wine during dinner for 4 weeks each. On the last day of each treatment period, blood was collected before and 1 h after a standardized dinner with red wine or de-alcoholized red wine and also 24-h urine was collected. Results: Absolute TEAC levels were higher 1 h after dinner with red wine compared with dinner with de-alcoholized red wine (1.3 versus 1.1 mmol Trolox equivalents/l; P = 0.03). Consumption of dinner together with de-alcoholized red wine acutely stimulated NF-κB activity in peripheral blood mononuclear cells (0.4-0.7 HeLa equivalents/2.5 μg protein; P = 0.006), whereas this increase was completely suppressed when the dinner was combined with red wine. A chronic increase in urinary 8-iso-PGF(2α) after 4 weeks of red wine consumption compared with de-alcoholized red wine consumption (157 pg/mg creatinine and 141 pg/mg creatinine, respectively, P = 0.006) was also observed. Conclusions: Consumption of a moderate dose of red wine can acutely increase plasma TEAC and suppress NF-κB activation induced by a meal. Controversially, 4 weeks of red wine consumption compared with de-alcoholized red wine consumption increases the oxidative lipid damage marker 8-iso-PGF(2α).
    Alcohol and Alcoholism 08/2012; DOI:10.1093/alcalc/ags086 · 2.09 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Alcohol binge-drinking (acute ethanol consumption) is immunosuppressive and alters both the innate and adaptive arms of the immune system. Antigen presentation by macrophages (and other antigen presenting cells) represents an important function of the innate immune system that, in part, determines the outcome of the host immune response. Ethanol has been shown to suppress antigen presentation in antigen presenting cells though mechanisms of this impairment are not well understood. The constitutive and immunoproteasomes are important components of the cellular proteolytic machinery responsible for the initial steps critical to the generation of MHC Class I peptides for antigen presentation. In this study, we used an cell culture model of acute alcohol exposure to study the effect of ethanol on the proteasome function in RAW 264.7 cells. Additionally, primary murine peritoneal macrophages obtained by peritoneal lavage from C57BL/6 mice were used to confirm our cell culture findings. We demonstrate that ethanol impairs proteasome function in peritoneal macrophages through suppression of chymotrypsin-like (Cht-L) proteasome activity as well as composition of the immunoproteasome subunit LMP7. Using primary murine peritoneal macrophages, we have further demonstrated that, ethanol-induced impairment of the proteasome function suppresses processing of antigenic proteins and peptides by the macrophage and in turn suppresses the presentation of these antigens to cells of adaptive immunity. The results of this study provide an important mechanism to explain the immunosuppressive effects of acute ethanol exposure.
    PLoS ONE 02/2013; 8(2):e56890. DOI:10.1371/journal.pone.0056890 · 3.53 Impact Factor