CYTOKINE-INDUCED EXPRESSION OF AN INDUCIBLE TYPE OF NITRIC-OXIDE SYNTHASE GENE IN CULTURED VASCULAR SMOOTH-MUSCLE CELLS

In unstimulated cultured vascular smooth muscle cells (VSMC), mRNA of an inducible macrophage-type of nitric oxide synthase (iNOS) was barely detectable. Interferon gamma (IFNgamma) and tumor necrosis factor alpha (TNFalpha) markedly increased iNOS mRNA levels in time- and dose-dependent manners. The induction of iNOS mRNA paralleled the cytokine-induced nitrite production. Actinomycin D abolished the IFNgamma- and TNFalpha-induced increases in iNOS mRNA and nitrite production. Cycloheximide, which abolished both the IFNgamma- and TNFalpha-induced increases in nitrite production, had no effect on the IFNgamma-induced increase in iNOS mRNA but markedly inhibited the TNFalpha-induced one. These results suggest that IFNgamma directly induces the expression of the iNOS gene whereas TNFalpha mainly induces it via the induction of an intermediary protein in cultured VSMC.