Alcohol reversibly disrupts TNF-alpha/TACE interactions in the cell membrane.
BACKGROUND
Alcohol abuse has long been known to adversely affect innate and adaptive immune responses and pre-dispose to infections. One cellular mechanism responsible for this effect is alcohol-induced suppression of TNF-alpha (TNF) by mononuclear phagocytes. We have previously shown that alcohol in part inhibits TNF-alpha processing by TNF converting enzyme (TACE) in human monocytes. We hypothesized that the chain length of the alcohol is critical for post-transcriptional suppression of TNF secretion.


METHODS
Due to the complex transcriptional and post-transcriptional regulation of TNF in macrophages, to specifically study TNF processing at the cell membrane we performed transient transfections of A549 cells with the TNF cDNA driven by the heterologous CMV promoter. TNF/TACE interactions at the cell surface were assessed using fluorescent resonance energy transfer (FRET) microscopy.


RESULTS
The single carbon alcohol, methanol suppressed neither TNF secretion nor FRET efficiency between TNF and TACE. However, 2, 3, and 4 carbon alcohols were potent suppressors of TNF processing and FRET efficiency. The effect of ethanol, a 2-carbon alcohol was reversible.


CONCLUSIONS
These data show that inhibition of TNF-alpha processing by acute ethanol is a direct affect of ethanol on the cell membrane and is reversible upon cessation or metabolism.
Song
Kejing
K
Gene Therapy Program, Alcohol Research Center, LSU Health Sciences Center, New Orleans, LA 70112, USA. ksong@chnola.org
Zhao
Xue-Jun
XJ
Marrero
Luis
L
Oliver
Peter
P
Nelson
Steve
S
Kolls
Jay K
JK
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D000438:Alcohols / Q000494:pharmacology; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology*; D006801:Humans; D000432:Methanol / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D025941:Protein Interaction Mapping; D011994:Recombinant Proteins / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000438:Alcohols; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; D000432:Methanol