Effect of acrolein on human alveolar macrophage NF-kappaB activity.
Acrolein is an environmental pollutant that is known to suppress respiratory host defense against infections; however, the mechanism of the decrease in host defense is not yet clear. We have previously reported that acrolein inhibited endotoxin-induced cytokine release and induced apoptosis in human alveolar macrophages, suggesting that the inhibition of cytokine release and/or cytotoxicity to alveolar macrophages may, in part, be responsible for acrolein-induced immunosuppression in the lung. Because nuclear factor-kappaB (NF-kappaB) is an important transcription factor for a number of cytokine genes and is also an important regulator of apoptosis, the effect of acrolein on NF-kappaB activity was examined by electrophoresis mobility shift assay. Acrolein caused a dose-dependent inhibition of endotoxin-induced NF-kappaB activation as well as an inhibition of basal level NF-kappaB activity. Because IkappaB is a principal regulator of NF-kappaB activity in the nucleus, changes in IkappaB were determined by Western blotting. Acrolein-inhibited IkappaB phosphorylation leads to an increase in cellular IkappaB levels preventing NF-kappaB nuclear translocation and is likely the mechanism of acrolein-induced inhibition of NF-kappaB activity. The role of basal level NF-kappaB in acrolein-induced apoptosis was also examined. An NF-kappaB inhibitor (MG-132) also induced apoptosis in human alveolar macrophages, suggesting that a certain basal level NF-kappaB activity may be required for macrophage cell survival. Taken together, our results suggest that the acrolein-inhibited endotoxin-induced NF-kappaB activation decreased the basal level NF-kappaB activity, which may be responsible for the inhibition of cytokine release and the induction of apoptosis in human alveolar macrophages.
Li
L
L
Toxicology Program, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Texas Houston Health Science Center, Houston, Texas 77030, USA.
Hamilton
R F
RF
Holian
A
A
D000171:Acrolein / Q000494:pharmacology*; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects
D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D000171:Acrolein