INDUCTION OF NITRIC-OXIDE SYNTHASE IN L929 CELLS BY TUMOR-NECROSIS-FACTOR-ALPHA IS PREVENTED BY INHIBITORS OF POLY(ADP-RIBOSE) POLYMERASE

The fibroblast cell line L929 contains a constitutively expressed NO synthase (EC 1.14.29.-) activity, which can be increased about 10-fold hy tumour-necrosis factor alpha (TNF-alpha). Activities of the conStitutive and the inducible enzymes are tetrahydrobiopterin-independent and can he inhibited by L-N(G)-nitroarginine. Induction of NO synthase by TNF-alpha was prevented by inhibitors of poly(ADP-ribose) polymerase. namely nicotinamide, 3-methoxybenzamide and 3-aminobenzamide. TNF-alpha did not lead to an increase in ADP-ribosyltransferase activity nor to a change in the pattern of ADP-ribosylated proteins. The inhibitors were only active during the first 4-5 h after exposure to TNF-alpha and they were found to suppress synthesis of protein, DNA and RNA. These data suggest that the inhibitors prevent induction of NO synthase by interference with RNA and protein synthesis. It is not yet known which reactions of these biosynthetic processes are affected by the inhibitors.