Induced nitric oxide inhibits IL-6-induced Stat3 activation and type II acute phase mRNA expression

Inducible nitric oxide synthase (iNOS) can be coexpressed with acute phase reactants in hepatocytes; however, it is unknown if NO can regulate the acu te 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 over expressed in cultured rat hepatocytes via transduction with a replication d efective adenovirus containing cDNA for human iNOS (AdiNOS), and Stat3 DNA- binding activity was determined by electrophoretic mobility shift assay (EM SA). 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-ind uced Stat3 activation and type II acute phase mRNA expression in cultured h epatocytes. This suppression may represent a mechanism by which NO down-reg ulates the acute phase response.