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Pyrrolidine Dithiocarbamate Inhibits Induction of Nitric Oxide Synthase Activity in Rat Alveolar Macrophages

https://doi.org/10.1006/bbrc.1993.1359Get rights and content

Abstract

Since nuclear factor kappa B (NF-κB) is activated during many inflammatory conditions, we assessed its role in expression of the L-arginine-nitric oxide pathway by rat alveolar macrophages. Pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB activation, was added to cultured macrophages stimulated with lipopolysaccharide (LPS) and interferon-γ (IFNγ). Inducible nitric oxide synthase (iNOS) activity was determined by measuring the stable nitrogen oxide end products of L-arginine oxidation: nitrite (NO2) and nitrate (NO3 ). Ten, 25 and 50 μM PDTC progressively inhibited iNOS activity by macrophages. When 50 μM PDTC was added 2 h before LPS + IFNγ, L-arginine oxidation by macrophages was inhibited by >99%; L-arginine oxidation was reduced by 70% if 50 μM PDTC and the stimuli were introduced together; NO2 and NO3 were not decreased significantly if 50 μM PDTC was added 6 h after LPS + IFNγ. Cycloheximide added along with LPS + IFNγ totally inhibits iNOS activity, while cycloheximide added 6 h after LPS + IFNγ did not reduce NO2 and NO3 in tissue culture supernatants. These findings suggest iNOS activity in macrophages treated with LPS + IFNγ requires NF-κB activation.

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