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International Immunology, Vol. 15, No. 11, pp. 1275-1282, November 2003
© 2003 Japanese Society for Immunology

FEATURED ARTICLE OF THE MONTH

Dominant-negative effect of the c-fos family gene products on inducible NO synthase expression in macrophages

Seiji Okada1,2, Shintaro Obata1, Masahiko Hatano1 and Takeshi Tokuhisa1

1 Department of Developmental Genetics (H2), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan 2 Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan

Correspondence to: T. Tokuhisa; E-mail: tokuhisa{at}med.m.chiba-u.ac.jp
Transmitting editor: T. Watanabe

Activation of murine peritoneal macrophages or the macrophage cell line RAW264 with IFN-{gamma} and bacterial lipopolysaccharide promotes a transient up-regulation of c-fos family gene expression following inducible NO synthase (iNOS) production. Since introduction of a double mutation into the two AP-1-binding sites in the iNOS promoter region reduced the promoter activity to 25% of the authentic one in activated RAW264 cells, the induced c-Fos/AP-1 may promote iNOS expression in activated macrophages. Surprisingly, overexpression of c-fos in activated macrophages completely suppressed the production of iNOS, but not that of IL-6 and IL-1ß. The regulatory effect was also observed by overexpression of c-fos, c-jun or fosB on the promoter activity as deduced from transfection experiments. However, the mutation of AP-1-binding sites in the promoter region did not abrogate the regulatory effect of c-fos and the effect of c-fos was diminished by co-transfection with c-jun, but not with fosB, suggesting no relation between the regulatory effect and a c-Fos/AP-1 complex. Expression of NF-IL6 (C/EBPß), whose gene product can make a non-functional heterodimer with c-Fos family proteins, was transiently induced in activated macrophages. Overexpression of NF-IL6 in activated RAW264 cells augmented iNOS promoter activity and reduced the regulatory effect of c-fos overexpression. Thus, overproduction of c-Fos family proteins acts as a dominant-negative-type regulator on iNOS expression in activated macrophages.

Keywords: monocyte/macrophage, NO, cellular activation, transcription factor


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