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 alpha (TNF-alpha) secretion. We investigated the mechanism of acute EtOH-induced TNF-alpha suppression in two monocytic cell lines, Mono Mac 6 and DRM. EtOH inhibited TNF-alpha secretion in a dose-dependent manner. However, TNF-alpha transcription was not affected by EtOH. Enzyme-linked immunosorbent assay and confocal microscopy showed that EtOH treatment increased cell-associated TNF-alpha. Ectodomain shedding of TNF-alpha from the cell surface is mediated by TNF-alpha converting enzyme (TACE). In contrast with TNF-alpha, 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-alpha production, resulting in specific defects in immune defense.
Zhang
Z
Z
Section of Pulmonary/Critical Care, Louisiana State Univerity Health Sciences Center, New Orleans, USA.
Cork
J
J
Ye
P
P
Lei
D
D
Schwarzenberger
P O
PO
Summer
W R
WR
Shellito
J E
JE
Nelson
S
S
Kolls
J K
JK
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D015703:Antigens, CD / Q000378:metabolism; D002460:Cell Line; D000431:Ethanol / Q000378:metabolism* / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology; D005434:Flow Cytometry / Q000379:methods; D015870:Gene Expression / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000378:metabolism* / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism; D007424:Intracellular Fluid / Q000378:metabolism; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal / Q000379:methods; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D015703:Antigens, CD; D007166:Immunosuppressive Agents; D016209:Interleukin-8; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein