Alcohol (ethanol) inhibits IL-8 and TNF: Role of the p38 pathway

Acute ethanol (EtOH) intoxication has been identified as a risk factor for infectious complications in trauma and burn victims, However, the mechanism of this immune dysfunction has yet to be elucidated, The monocyte/macropha ge production of cytokines, in particular IL-8 and TNF-alpha, is critical i n the regulation of the acute inflammatory response to infectious challenge , IL-8 is a patent chemoattractant and activator of neutrophils, TNF-alpha, a proinflammatory cytokine, initiates expression of endothelial cell surfa ce adhesion molecules and neutrophil migration, p38, a member of the mitoge n-activated protein kinases, plays an important role in mediating intracell ular signal transduction in endotoxin-induced inflammatory responses. We ex amined the effects of LPS and ethanol on p38 activation and the correspondi ng IL-8 and TNF-alpha production in human mononuclear cells. LPS-induced IL -8 and TNF-alpha production was inhibited in a similar pattern by pretreatm ent with either EtOH or SB202190 (1 mu M), a specific inhibitor of p38 kina se, Western blot analysis, using a dual phospho-specific p38 mitogen-activa ted protein kinase Ab, demonstrated that EtOH pretreatment inhibited LPS-in duced p38 activation, These results demonstrate that alcohol suppresses the normal host immune inflammatory response to LPS, This dysregulation appear s to be mediated in part via inhibition of p38 activation. Inhibition of IL -8 and TNF-alpha production by acute EtOH intoxication may inhibit inflamma tory focused neutrophil migration and activation and may be a mechanism exp laining the increased risk of trauma- and burn-related infections.