N -Acetyl- l -Cysteine Potentiates Interleukin-1β Induction of Nitric Oxide Synthase

—We have reported previously thatN -acetyl-l -cysteine facilitated interleukin-1β–induced nitric oxide synthase (iNOS) expression in rat vascular smooth muscle cells. The present study compares the effect ofN -acetyl-l -cysteine with other antioxidants and tested the possibility thatN -acetyl-l -cysteine potentiates iNOS induction by a mechanism involving activation of p44/42 mitogen-activated protein kinases (MAPKs). The effect ofN -acetyl-l -cysteine on potentiating interleukin-1β–induced nitrite production and iNOS expression was mimicked either by the enantiomers,l -cysteine andd -cysteine, or by a non–thiol-containing antioxidant,l -ascorbic acid. Interleukin-1β activated p44/42 MAPK, and this activation was enhanced in the presence ofN -acetyl-l -cysteine. Inhibition of p44/42 MAPK phosphorylation by the selective inhibitor PD98059 clearly inhibited iNOS expression induced by interleukin-1β either in the absence or in the presence ofN -acetyl-l -cysteine. These observations, combined with previous results, indicate that p44/42 MAPK activation is required for interleukin-1β induction of iNOS and thatN -acetyl-l -cysteine may act as a reducing agent and facilitate interleukin-1β–induced iNOS expression through a reduction/oxidation-related mechanism involving potentiation of cytokine activation of the p44/42 MAPK signaling pathway.