Differential effects of in vivo ethanol on LPS-induced TNF and nitric oxide production in the lung.
Alcohol (EtOH) has been shown to suppress lipopolysaccharide (LPS)-induced nitric oxide (NO) generation and tumor necrosis factor (TNF) production in the lung in vivo. We have previously reported that EtOH suppressed gene expression for inducible nitric oxide synthase (iNOS) with a subsequent decrease in release of reactive nitrogen intermediates by alveolar macrophages and recruited lung neutrophils. We hypothesized that a similar mechanism may be involved in EtOH-induced suppression of LPS-stimulated TNF production. In contrast to what we found with iNOS, EtOH had no effect on TNF mRNA in alveolar macrophages or recruited lung neutrophils. However, immunoreactive and bioactive TNF was reduced by 72%. EtOH treatment resulted in an increased level of the membrane-bound 26-kDa form of TNF, which suggested that proteolytic cleavage of this prohormone was affected by EtOH. Experiments with t-butyl alcohol, a tertiary alcohol that is not metabolized to acetaldehyde, yielded similar results. Thus EtOH appears to be the active substance in suppression of TNF in the lung in vivo. Pretreatment with intratracheal interferon-gamma 24 h before intratracheal LPS increased TNF bioactivity partly due to increased TNF mRNA and by increasing TNF processing, as evidenced by a decrease in the 26-kDa TNF prohormone and an increase in immunoreactive and bioactive TNF.
Kolls
J K
JK
Louisiana State University Section of Pulmonary/Critical Care, New Orleans 70112, USA.
Xie
J
J
Lei
D
D
Greenberg
S
S
Summer
W R
WR
Nelson
S
S
D000435:Alcoholic Intoxication / Q000378:metabolism*; D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis; D000818:Animals; D001483:Base Sequence; D001681:Biological Assay; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D000440:Butanols / Q000494:pharmacology; D017931:DNA Primers; D004790:Enzyme Induction; D000431:Ethanol / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D007739:L Cells; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D046911:Macromolecular Substances; D008297:Male; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis* / Q000494:pharmacology; D020002:tert-Butyl Alcohol
D000440:Butanols; D017931:DNA Primers; D008070:Lipopolysaccharides; D046911:Macromolecular Substances; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D000431:Ethanol; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D020002:tert-Butyl Alcohol