Regulation of lipopolysaccharide-mediated interleukin-1beta release by N-acetylcysteine in THP-1 cells.
Increased levels of inflammatory cytokines such as interleukin (IL)-1 and IL-8 occur in the bronchoalveolar lavage fluid in various lung diseases. Cytokine gene expression is controlled by transcription factors such as nuclear factor-kappaB (NF-kappaB) which can be activated by a number of stimuli including the oxidants prevent. It was hypothesized that lipopolysaccharide (LPS)-induced IL-1beta secretion may be modulated by the intracellular thiol redox status of the cells. The effect of the antioxidant compound, N-acetyl-L-cysteine (NAC), on IL-1beta release and regulation of NF-kappaB in a human myelo-monocytic cell line (THP-1) differentiated into macrophages was studied. LPS (10 microg x mL(-1)) increased IL-1beta release at 24 h compared to control levels (p<0.001). NAC (5 mM) also enhanced LPS-induced IL-1beta release from THP-1 cells (p<0.001). In addition, treatment of cells with cycloheximide, an inhibitor of protein synthesis, inhibited the NAC-mediated IL-1beta release. Under the same conditions, NF-kappaB binding was activated by LPS and NAC increased this LPS-mediated effect. Western blot analysis revealed that NAC treatment leads to an increase in p50 and p65 protein synthesis. These data indicate that N-acetyl-L-cysteine modulates interleukin-1kappa release by increasing levels of the homo- and heterodimeric forms of nuclear factor-kappaB.
Parmentier
M
M
Dept of Medicine, University of Edinburgh Medical School, UK.
Hirani
N
N
Rahman
I
I
Donaldson
K
K
MacNee
W
W
Antonicelli
F
F
D000111:Acetylcysteine / Q000494:pharmacology*; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology; D019319:Okadaic Acid / Q000494:pharmacology; D020033:Protein Isoforms / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism
D004791:Enzyme Inhibitors; D007375:Interleukin-1; D008070:Lipopolysaccharides; D016328:NF-kappa B; D020033:Protein Isoforms; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D019319:Okadaic Acid; C042431:S-ethyl glutathione; D003513:Cycloheximide; D005978:Glutathione; D000111:Acetylcysteine