Journal
SHOCK
Volume 13, Issue 6, Pages 441-445Publisher
BIOMEDICAL PRESS
DOI: 10.1097/00024382-200006000-00004
Keywords
inducible nitric oxide synthase; Stat3; beta-fibrinogen; hepatocytes; interleukin 6; adenoviral vector
Funding
- NHLBI NIH HHS [HL 32154] Funding Source: Medline
- NIGMS NIH HHS [P50-GM-53789, GM-37753] Funding Source: Medline
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Inducible nitric oxide synthase (iNOS) can be coexpressed with acute phase reactants in hepatocytes; however, it is unknown if NO can regulate the acute phase response. We tested the hypothesis that iNOS-derived nitric oxide (NO) attenuates the acute phase response by inhibiting IL-6-enhanced Stat3 DNA-binding activity and type II acute phase mRNA expression. iNOS was overexpressed in cultured rat hepatocytes via transduction with a replication defective adenovirus containing cDNA for human iNOS (AdiNOS), and Stat3 DNA-binding activity was determined by electrophoretic mobility shift assay (EMSA). EMSAs demonstrated that AdiNOS inhibits IL-6-induced Stat3 activation and that this inhibition is reversible in the presence of the NOS inhibitor NG-monomethyl-L-arginine (L-NMA). The induction of P-fibrinogen mRNA by IL-6, a Stat3 dependent process, is attenuated in AdiNOS-transduced cells and partially reversed by L-NMA. Thus, iNOS overexpression suppresses IL-6-induced Stat3 activation and type II acute phase mRNA expression in cultured hepatocytes. This suppression may represent a mechanism by which NO down-regulates the acute phase response.
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