The inhibitory effect of interleukin 1beta on rat hepatocyte DNA synthesis is mediated by nitric oxide.
Interleukin 1beta (IL-1beta) 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-1beta in a dose-dependent manner. IL-1beta also induced NO production and inducible NO synthase (iNOS) gene expression. The inhibition of DNA synthesis by IL-1beta was completely abrogated when NO production was inhibited by N-monomethyl-L-arginine (NMA), a competitive inhibitor of iNOS. IL-1beta-receptor antagonist (IL-1ra), which interferes with the interaction of IL-1beta with target cells, also abolished the inhibitory effects of IL-1beta on hepatocyte DNA synthesis as well as IL-1beta-induced iNOS gene expression. We also found that hepatocyte DNA synthesis inhibition by IL-1beta 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-1beta. These experiments extended prior observations on the growth-inhibitory actions of IL-1beta on hepatocyte DNA synthesis, involving the IL-1beta receptor, NO production, and ribonucleotide reductase.
Thomas E. Starzl Transplant Institute, Department of Surgery, University of Pittsburgh School of Medicine, PA 15213, USA.
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D000818:Animals; D002478:Cells, Cultured; D004247:DNA / Q000037:antagonists & inhibitors*; D004789:Enzyme Activation / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D007375:Interleukin-1 / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D012264:Ribonucleotide Reductases / Q000378:metabolism; D019323:omega-N-Methylarginine / Q000494:pharmacology
D007375:Interleukin-1; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D004247:DNA; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D012264:Ribonucleotide Reductases