[The synergistic effect of interferon-gamma on the induction of nitric oxide synthase by lipopolysaccharide in vascular smooth muscle].

Abstract

Bacterial lipopolysaccharide (LPS) and other immunostimulants induce an isoform of nitric oxide synthase (iNOS) in vascular smooth muscle (VSM) which produces large quantities of nitric oxide (NO) and profound vasodilation. This process has been implicated as the cause of gram-negative septic shock. It has been demonstrated that interferon-gamma (IFN) markedly potentiates cytokine-induced NO synthesis in various cell types. However, little is known about the mechanism of this enhancing effect of IFN. The present study was undertaken to investigate the effect of IFN on LPS-induced NO synthesis and iNOS mRNA expression in VSM and the possibility of nuclear factor kB (NFkB) involvement in the effect of IFN. LPS-induced NO synthesis is markedly potentiated by IFN in VSM. Expression of iNOS mRNA in VSM costimulated with IFN and LPS was greatly increased compared to that induced by LPS alone. IFN did not alter the lifetime of iNOS mRNA. LPS stimulated translocation into the nuclei of NFkB which is believed to play an important role in the induction of iNOS, but IFN did not enhance NFkB activation by LPS. These results suggest that the enhancing effect of IFN is due to the increased transcription of the iNOS gene rather than a decreased degradation of iNOS mRNA and that the NFkB activation pathway is not involved in this effect of IFN.