N-Acetyl-L-cysteine potentiates interleukin-1beta induction of nitric oxide synthase : role of p44/42 mitogen-activated protein kinases.
We have reported previously that N-acetyl-L-cysteine facilitated interleukin-1beta-induced nitric oxide synthase (iNOS) expression in rat vascular smooth muscle cells. The present study compares the effect of N-acetyl-L-cysteine with other antioxidants and tested the possibility that N-acetyl-L-cysteine potentiates iNOS induction by a mechanism involving activation of p44/42 mitogen-activated protein kinases (MAPKs). The effect of N-acetyl-L-cysteine on potentiating interleukin-1beta-induced nitrite production and iNOS expression was mimicked either by the enantiomers, L-cysteine and D-cysteine, or by a non-thiol-containing antioxidant, L-ascorbic acid. Interleukin-1beta activated p44/42 MAPK, and this activation was enhanced in the presence of N-acetyl-L-cysteine. Inhibition of p44/42 MAPK phosphorylation by the selective inhibitor PD98059 clearly inhibited iNOS expression induced by interleukin-1beta either in the absence or in the presence of N-acetyl-L-cysteine. These observations, combined with previous results, indicate that p44/42 MAPK activation is required for interleukin-1beta induction of iNOS and that N-acetyl-L-cysteine may act as a reducing agent and facilitate interleukin-1beta-induced iNOS expression through a reduction/oxidation-related mechanism involving potentiation of cytokine activation of the p44/42 MAPK signaling pathway.
Jiang
B
B
Department of Biochemistry and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA.
Brecher
P
P
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000201:enzymology*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017208:Rats, Wistar
D016166:Free Radical Scavengers; D007375:Interleukin-1; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D000111:Acetylcysteine