Share this article on:

INDUCED NITRIC OXIDE INHIBITS IL-6-INDUCED STAT3 ACTIVATION AND TYPE II ACUTE PHASE MRNA EXPRESSION

Villavicencio, Raphael T.; Liu, Shubing; Kibbe, Melina R.; Williams, Debra L.; Ganster, Raymond W.; Dyer, Kevin F.; Tweardy, David J.; Billiar, Timothy R.; Pitt, Bruce R.
Shock: June 2000
Basic Science Investigations: PDF Only

ABSTRACT

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 β-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.

Received 8 Feb 1999; first review completed 25 Feb 1999; accepted in final form 22 Dec 1999

Address reprint requests to Bruce R. Pitt. PhD, Department of Pharmacology. University of Pittsburgh, Pittsburgh, Pennsylvania 15261.

©2000The Shock Society