N-Acetyl-L-Cysteine Potentiates Interleukin-1b Induction of Nitric Oxide Synthase Role of p44/42 Mitogen-Activated Protein Kinases

We have reported previously that N-acetyl-L-cysteine facilitated interleukin-1b–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-1b–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-1b 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-1b 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-1b induction of iNOS and that N-acetyl-L-cysteine may act as a reducing agent and facilitate interleukin-1b–induced iNOS expression through a reduction/oxidation-related mechanism involving potentiation of cytokine activation of the p44/42 MAPK signaling pathway. (Hypertension. 2000;35:914-918.)