Suppressive role of c-fos in the iNOS expression of macrophages

Abstract

Abstract The proto-oncogene c- fos is transiently expressed in various kinds of cells except for macrophages (Mφ) by external stimuli, and works as a component of AP-1. Murine peritoneal Mφ and Mφ like cell line, RAW 264 constitutively expressed c- fos mRNA, which produce nitric oxide (NO) by external stimuli and fall into apoptosis. To investigate the role of c- fos in Mφ, we used transgenic mice carrying the c- fos gene under the control of the interferon-α/β inducible Mx-promoter (Mx-c-fos). By the stimulation in IFN-γ and LPS, c- fos expression was down-regulated within one hour after stimulation after transient up-regulation and returned to the previous level after 6 hours. Inducible nitric oxide synthase (iNOS) expression was observed after the down-regulation of c- fos . Over-expression of the c- fos in the Mx-c-fos mice derived Mφ inhibited iNOS mRNS expression and NO production whereas the IL-1 and IL-6 production were not inhibited, indicated that down-regulation of c- fos is needed for the iNOS expression. Luciferase assay revealed c- fos suppressed NF-IL-6 dependent iNOS promoter activity. As NF-IL-6 is known to be a strong activator of iNOS and make heterodimer with c- fos , c- fos may suppress iNOS expression not by AP-1 complex but by neutrization of NF-IL-6 activity. These results suggest that constitutively expressed c- fos may inhibit the accidental expression of iNOS expression and works as the stabilizer of Mφ.