title: Acute alcohol inhibits TNF-alpha processing in human monocytes by inhibiting TNF/TNF-alpha-converting enzyme interactions in the cell membrane.
abstract: Alcohol abuse has long been known to adversely affect innate immune responses and predispose to infections. One cellular mechanism responsible for this effect is alcohol-induced suppression of TNF-alpha by mononuclear phagocytes. We undertook experiments to better understand the cellular mechanisms by which alcohol dose-dependently suppresses TNF elaboration by human monocytes. Here we show in human primary monocytes and cell lines that alcohol suppresses LPS-induced TNF secretion post-transcriptionally by inhibiting cellular processing by TNF-alpha-converting enzyme (TACE). Using fluorescent resonance energy transfer microscopy, physiological relevant levels of alcohol resulted in a reversible dose-dependent decrease in fluorescent resonance energy transfer efficiency between TNF and TACE. These data demonstrate that alcohol inhibits interactions between TNF and its converting enzyme, TACE, possibly by affecting membrane fluidity. These data in part explain the cellular mechanisms by which alcohol impairs monocyte function and may identify immunotherapeutic targets aimed at restoring immune function in this at-risk patient population.
authors.affiliation: Gene Therapy Program and Alcohol Research Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Xue-Jun
authors.initials: XJ
authors.lastname: Zhao
authors.forename: Luis
authors.initials: L
authors.lastname: Marrero
authors.forename: Kejing
authors.initials: K
authors.lastname: Song
authors.forename: Peter
authors.initials: P
authors.lastname: Oliver
authors.forename: So Yeon
authors.initials: SY
authors.lastname: Chin
authors.forename: Harriet
authors.initials: H
authors.lastname: Simon
authors.forename: Jill R
authors.initials: JR
authors.lastname: Schurr
authors.forename: Zili
authors.initials: Z
authors.lastname: Zhang
authors.forename: Deepu
authors.initials: D
authors.lastname: Thoppil
authors.forename: Sharon
authors.initials: S
authors.lastname: Lee
authors.forename: Steve
authors.initials: S
authors.lastname: Nelson
authors.forename: Jay K
authors.initials: JK
authors.lastname: Kolls
mesh_terms: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D002478:Cells, Cultured; D000431:Ethanol / Q000633:toxicity*; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D007166:Immunosuppressive Agents / Q000633:toxicity*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects* / Q000276:immunology*; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse