Interleukin 1β (IL-Iβ) and nitric oxide (NO) have potent growth- regulatory effects on different cell types. We found that epidermal growth factor-induced DNA synthesis in primary cultures of adult rat hepatocytes 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-1β in a dose-dependent manner. IL-1β also induced NO production and inducible NO synthase (iNOS) gene expression. The inhibition of DNA synthesis by IL-1β was completely abrogated when NO production was inhibited by N- monomethyl-L-arginine (NMA), a competitive inhibitor of iNOS. IL-lβ-receptor antagonist (IL-1ra), which interferes with the interaction of IL-1β with target cells, also abolished the inhibitory effects of IL-Iβ on hepatocyte DNA synthesis as well as IL-1β-induced iNOS gene expression. We also found that hepatocyte DNA synthesis inhibition by IL-1β was completely antagonized by providing deoxynucleosides to bypass the block in ribonucleotide reductase, a rate-limiting step in DNA synthesis, thus implicating this enzyme in the mechanism of growth inhibition by IL-1β. These experiments extended prior observations on the growth-inhibitory actions of IL-1β on hepatocyte DNA synthesis, involving the IL-1β receptor, NO production, and ribonucleotide reductase.
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