Effects of hepatocellular mitogens on cytokine-induced nitric oxide synthesis in human hepatocytes

Zhi Ze Liu, Shijun Cui, Timothy R. Billiar, Kenneth Dorko, Willi Halfter, David A. Geller, George Michalopoulos, Hans G. Beger, Jorge Albina, Andreas K. Nussler*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


The synthesis of induced nitric oxide (NO) is regulated by several cytokines, including growth factors produced following hepatic injury and inflammation. However, little information is available on the role of growth factors in regulating the inducible NO synthase in human hepatocytes. The capacity of hepatocellular mitogens (HGF, EGF, and TGF-α) to regulate the inducible NO synthase (iNOS) was studied in human hepatocytes incubated with inflammatory cytokines and lipopolysaccharide (LPS). Furthermore, the effects of hepatic mitogens on NO-induced changes in DNA and protein synthesis was studied. It was found that NO-mediated decrease of protein and DNA synthesis were partially reversed by the mitogens. This was associated with a downregulation in cytokine-mediated hepatocyte NO formation, iNOS mRNA expression, and NOS enzyme activity. Cytokine-induced NO formation or SNAP, an NO donor, added with cytokines increased hepatocyte chromatin condensation but no DNA fragmentation was observed. The increase in chromatin condensation was partially reversed by hepatic mitogens and corresponded with the inhibition of NO production. Thus, the hepatic mitogens, HGF, EGF, and TGF-α, all suppress iNOS expression and it is the suppression of iNOS that appears to be responsible for the mitogen-reduced preservation of DNA and protein synthesis and prevention of chromatin condensation.

Original languageEnglish
Pages (from-to)382-388
Number of pages7
JournalJournal of Leukocyte Biology
Issue number3
StatePublished - Sep 1996
Externally publishedYes


  • Growth factors
  • Hepatc regeneration
  • Inflammation
  • Sepsis


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