Acute alcohol regulation of inflammatory cytokine production in human monocytes: A role for NF-B

Abstract

Decreased tumor necrosis factor,~ (TNF~) production is a major contributor to decreased host defense after acute alcohol consumption. We have previously shown that in vitro acute alcohol treatment decreases monocyte tumor necrosis factorot TNF, x and interleukin-l(IL-1) production at the protein and the mRNA levels. Here we show that in vivo consumption of acute alcohol (2ml vodka/kg body weight; BAL:.lg/dl) by nonalcoholic healthy individuals also significantly decreases TNF~x and IL-I~ production in ex vivo challenged isolated blood monocytes (p<0.01). However, the intracellular mechanisms for down-regulation of bacterial stimulation-induced IL-11] and TNF,~ production in MO after in vivo or in vitro acute alcohol treatment are yet to be dissected. Here, NF-kB/Rel was tested as a potential target for ethanol in regulation of inflammatory cytokine gene expression. We have previously reported a rapid decrease in mRNA and protein levels of the NF-KB-regulated inflammatory cytokines in M~3 after acute ethanol treatment. Minimal NF-~B binding was seen in unstimulated M~3 from non-alcoholic donors. M~3 activation with l~tg/ml LPS substantially increased NF-kB binding of both the p65/p50 and p50/p50 dimers as early as 30 min and as late as 24 hrs after stimulation. In contrast, acute ethanol(25mM) treatment resulted in preferential induction of p50/p50 homodimer as determined in supershifts utilizing antihuman p50 and p65 antibodies. Further, ethanol prevented p65/p50 heterodimer induction by LPS in M~3. Differential NF-~B/Rel dimer induction by ethanol was confirmed by Western blots where ethanol induced only p50 nuclear translocation versus both p50 and p65 translocation after LPS. These results suggest that acute ethanol induces nuclear translocation of different NF-~B/Rel dimers compared to LPS. Thus, preferential induction of p50 homodimers by ethanol, which have negative regulatory capacity on NF-KB-driven gene induction, may result in increased NF-KB/Rel DNA binding without gene activation thereby preventing bacterial stimulationinduced TNF~ and IL-113 gene induction in human monocytes. Consequently, acute ethanol exposure blunts inflammatory mediator production in response to subsequent bacterial stimuli. Further, acute ethanol may interfere with progression of diseases including Hepatitis C infection where activation of inflammation-related NF-~B-driven gene products is critical for progression of the disease.