Dinghua Lei

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

Alcohol (EtOH) is a well‐documented immunosuppressant. Acute EtOH‐induced immunosuppression is partially due to suppression of tumor necrosis factor α (TNF‐α) secretion. We investigated the mechanism of acute EtOH‐induced TNF‐α suppression in two monocytic cell lines, Mono Mac 6 and DRM. EtOH inhibited TNF‐α secretion in a dose‐dependent manner. However, TNF‐α transcription was not affected by EtOH. Enzyme‐linked immunosorbent assay and confocal microscopy showed that EtOH treatment increased cell‐associated TNF‐α. Ectodomain shedding of TNF‐α from the cell surface is mediated by TNF‐α converting enzyme (TACE). In contrast with TNF‐α, EtOH did not inhibit interleukin‐8 (IL‐8) secretion, which does not require shedding. Furthermore, TNF p75 receptor shedding, a biomarker for TACE activity, was inhibited by EtOH in both cell lines. EtOH also inhibited TNF p75 receptor shedding in TACE‐reconstituted fibroblasts, suggesting that EtOH inhibits the shedding process. These data show that acute EtOH exposure can posttranscriptionally suppress TNF‐α production, resulting in specific defects in immune defense. J. Leukoc. Biol. 67: 856–862; 2000.