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

Abstract

Alcohol (EtOH) is a well-documented immunosuppressant. Acute EtOH-induced immunosuppression is partially due to suppression of tumor necrosis factor ␣ (TNF-␣) secretion. We investigated the mechanism of acute EtOH-induced TNF-␣ suppression in two monocytic cell lines, Mono Mac 6 and DRM. EtOH inhibited TNF-␣ secretion in a dosedependent manner. However, TNF-␣ transcription was not affected by EtOH. Enzyme-linked immunosorbent assay and confocal microscopy showed that EtOH treatment increased cell-associated TNF-␣. Ectodomain shedding of TNF-␣ from the cell surface is mediated by TNF-␣ converting enzyme (TACE). In contrast with TNF-␣, 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-␣ production, resulting in specific defects in immune defense.

Acute Alcohol Inhibits TNF-α Processing in Human Monocytes by Inhibiting TNF/TNF-α-Converting Enzyme Interactions in the Cell Membrane

“…1D). These data are in agreement with our prior published observations in Mono Mac 6 cells, where acute EtOH did not inhibit LPS/PMA-induced increases in steady-state TNF mRNA levels or mRNA half-life (15).…”

“…However, in these studies, steady-state transcripts for TNF mRNA were suppressed between 20 -30% in association with a Ͼ70% reduction in protein (32). Moreover, studies from our laboratory in human Mono Mac 6 cells and primary primate macrophages have shown that TNF transcription, steady-state mRNA transcripts, and TNF mRNA half-life are not altered by acute EtOH (14,15). Thus, we investigated whether there exists a significant post-transcriptional/ post-translational effect of acute EtOH on TNF production as well.…”

“…It is important to note that this study focused on the effects of acute EtOH, which has been shown to suppress TNF production in a variety of human and rodent models (9,10,15,32). We did not investigate the effect of chronic EtOH.…”

“…Szabo and colleagues (7,11) have reported decreased nuclear translocation of NF-B and reduced steady-state levels of TNF mRNA in alcoholexposed human monocytes. Studies in our laboratory have also shown a significant post-transcriptional and post-translational component of acute alcohol-mediated TNF suppression in both rodent and primate macrophages (12)(13)(14)(15). Based on these studies we hypothesized that acute EtOH results in decreased processing of TNF by TNF-␣-converting enzyme (TACE), a member of the disintegrin and metalloproteinase (ADAM) family of proteins (16,17).…”

Microbial Infections, Immunomodulation, and Drugs of Abuse

“…In addition, alcohol suppresses the production of cytokines important in antimicrobial immunity, such as TNF-␣ secreted by mononuclear cells in vitro and/or in vivo, including alveolar macrophages from rats (114,160) and rhesus macaques (226). The suppression of TNF-␣ is posttranscriptional and involves TNF-␣-converting enzyme-mediated processing of TNF-␣ (114,267). Furthermore, in human monocytes, alcohol inhibits lipopolysaccharide LPS-induced activation of NF-B, a transcription factor for inflammatory cytokines (129).…”