Inhibition of TNF-alpha processing and TACE-mediated ectodomain shedding by ethanol

Alcohol (EtOH) is a well-documented immunosuppressant. Acute EtOH-induced i mmunosuppression is partially due to suppression of tumor necrosis factor a lpha (TNF-alpha) secretion. We investigated the mechanism of acute EtOH-ind uced TNF-alpha suppression in two monocytic tell Lines, Mono Mac 6 and DRM, EtOH inhibited TNF-alpha secretion in a dose-dependent manner. However, TN F-alpha transcription was not affected by EtOH, Enzyme-linked immunosorbent assay and confocal microscopy showed that EtOH treatment increased cell-as sociated TNF-alpha. Ectodomain shedding of TNF-alpha from the cell surface is mediated by TNF-alpha converting enzyme (TACE), In contrast with TNF-alp ha, EtOH did not inhibit interleukin-8 (IL-8) secretion, which does not req uire shedding. Furthermore, TNF p75 receptor shedding, a biomarker for TACE activity, was inhibited by EtOH in both cell lines. EtOH also inhibited TN F p75 receptor shedding ill TACE-reconstituted fibroblasts, suggesting that EtOW inhibits the shedding process. These data show that acute EtOH exposu re can posttranscriptionally suppress TNF-alpha production, resulting in sp ecific defects in immune defense.