THE INHIBITORY EFFECT OF INTERLEUKIN-1-BETA ON RAT HEPATOCYTE DNA-SYNTHESIS IS MEDIATED BY NITRIC-OXIDE

Interleukin 1 beta (IL-1 beta) and nitric oxide (NO) have potent growt h-regulatory effects on different cell types, We found that epidermal growth factor-induced DNA synthesis in primary cultures of adult rat h epatocytes was inhibited by NO when it was provided by addition to the cultures of S-nitroso-N-acetyl-penicillamine (SNAP), an NO donor, as well as by addition of IL-1 beta in a dose-dependent manner, IL-1 beta also induced NO production and inducible NO synthase (iNOS) gene expr ession. The inhibition of DNA synthesis by IL-1 beta was completely ab rogated when NO production was inhibited by N-monomethyl-L-arginine (N MA), a competitive inhibitor of iNOS, IL-1 beta-receptor antagonist (I L-1ra), which interferes with the interaction of IL-1 beta with target cells, also abolished the inhibitory effects of IL-1 beta on hepatocy te DNA synthesis as well as IL-1 beta-induced iNOS gene expression. We also found that hepatocyte DNA synthesis inhibition by IL-1 beta was completely antagonized by providing deoxynucleosides to bypass the blo ck in ribonucleotide reductase, a rate-limiting step in DNA synthesis, thus implicating this enzyme in the mechanism of growth inhibition by IL-1 beta. These experiments extended prior observations on the growt h-inhibitory actions of IL-1 beta on hepatocyte DNA synthesis, involvi ng the IL-1 beta receptor, NO production, and ribonucleotide reductase .