N -Acetyl- l -Cysteine Enhances Interleukin-1β–Induced Nitric Oxide Synthase Expression

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Abstract
—The effect of N -acetyl- l -cysteine on interleukin-1β–induced nitric oxide synthase expression was studied in rat vascular smooth muscle cells to determine if the reduction/oxidation state would modulate cytokine-induced changes. Interleukin-1β induced the production of nitrite, a stable metabolite of nitric oxide in a time- and dose-dependent manner. Cytokine-induced nitrite production was enhanced by the addition of N -acetyl- l -cysteine in a dose-dependent manner, with a >50% increase produced by the addition of 1 mmol/L N- acetyl- l -cysteine. There was no influence on nitrite production when the cells were treated with N -acetyl- l -cysteine alone. Northern and Western blot analyses revealed that the upregulation of interleukin-1β–induced nitric oxide production by N -acetyl- l -cysteine resulted from an enhanced expression of inducible nitric oxide synthase. Interferon-γ or tumor necrosis factor-α when used alone had no influence on nitrite production in the absence or presence of N- acetyl- l -cysteine. Nitrite accumulation was higher by the cells treated with interleukin-1β combined with either interferon-γ or tumor necrosis factor-α compared with those treated with interleukin-1β alone. N -Acetyl- l -cysteine upregulated nitrite production and inducible nitric oxide synthase expression induced by combination treatment with interleukin-1β and either interferon-γ or tumor necrosis factor-α. However, N -acetyl- l -cysteine had no significant influence in cytokine-induced activation of nuclear factor-κB or signal transducer and activator of transciption-1, as assessed by electrophoretic mobility shift assays. These results demonstrate that N- acetyl- l -cysteine possibly acted as a thiol-containing reducing agent and facilitated the expression of inducible nitric oxide synthase in rat vascular smooth muscle cells by cytokines through a mechanism that is independent of nuclear factor-κB or signal transducer and activator of transciption-1.