Requirement for Transcription Factor IRF-1 in NO Synthase Induction in Macrophages

Abstract

Production of nitric oxide (NO) by macrophages is important for the killing of intracellular infectious agents. Interferon (IFN)-gamma and lipopolysaccharide stimulate NO production by transcriptionally up-regulating the inducible NO synthase (iNOS). Macrophages from mice with a targeted disruption of the IFN regulatory factor-1 (IRF-1) gene (IRF-1-/- mice) produced little or no NO and synthesized barely detectable iNOS messenger RNA in response to stimulation. Two adjacent IRF-1 response elements were identified in the iNOS promoter. Infection with Mycobacterium bovis (BCG) was more severe in IRF-1-/- mice than in wild-type mice. Thus, IRF-1 is essential for iNOS activation in murine macrophages.

Activation and repression of the 2-5A synthetase and p21 gene promoters by IRF-1 and IRF-2

“…Several studies have demonstrated the role of IRF-1 and IRF-2 factors in the regulation of IFN type I genes (Matsuyama et al, 1993;Kamijo et al, 1994;Kimura et al, 1994); less clear is the direct role of IRFs in the regulation of cell growth. We analysed in particular the regulation of two genes potential target of the IFN-g induced growth inhibition mediated by IRFs: the 2-5A synthetase directly involved in the IFNmediated growth inhibition and the cell-cycle inhibitor p21 (WAF/CP1).…”

Anti-inflammatory action of type I interferons deduced from mice expressing interferon β

“…[9][10][11] Multiple proinflammatory cytokines and bacterial cell wall products are involved in the expression of iNOS, acting in a concerted cooperative pathway. [12][13][14] The synergism between lipopolysaccharide (LPS) and IFN-␥ in the transactivation of the inducible iNOS promoter has been well documented using mice lacking molecules involved in the intracellular signaling of IFN-␥, [15][16][17] and this synergistic ity after eliciting with thioglycollate broth. The expression of the inducible form of nitric oxide synthase and cyclooxygenase-2, two enzymes involved in inflammation, was impaired in transgenic animals challenged with lipopolysaccharide and IFN-␥.…”

Cooperative activity between HER oncogenes and the tumor suppressor IRF-1 results in apoptosis

“…IRF-1 induces IFN stimulated genes, e.g. MHC class I (Hobart et al, 1996;Salkowski et al, 1996), iNOS (Kamijo et al, 1994) and GBP (Briken et al, 1995). IRF-1 is also necessary for proper expression of IL-15 (Ogasawara et al, 1998), p21 (Tanaka et al, 1996), and IFN-b (Fujita et al, 1993).…”