Control of Inducible Nitric Oxide Synthase Gene Expression by Interferon Regulatory Factor-1: Implications for Host Resistance to Bacteria and Viruses
Interferon regulatory factors (IRF)-1 and -2 were originally identified as transcription factors involved in the induced expression of IFN-β genes by Miyamoto et al. (1988). These authors used regulatory DNA sequences identified in the promoter of the IFN-β gene to purify proteins isolated from the nuclei of cells stimulated to produce IFN-β. One protein shown to bind to sequences in the 5′-flanking region of the IFN-β gene was termed IRF-1. Genes for IRF-1 and the structurally related protein, IRF-2, were also identified and cloned. A number of subsequent studies showed that IRF-1 acted as a transcriptional activator, whereas IRF-2 inhibited transcription (Harada et al. 1990). Perhaps the best evidence showing that IRF-1 plays a role in IFN induction was provided by the finding that cDNA-directed expression of IRF-1 (but not of IRF-2) led to transcriptional activation of endogenous IFN-α and -β genes in two types of cells (Fujita et al. 1989 a; Harada et al. 1990). These findings, along with the demonstration that treatments which increase IFN-β mRNA levels also increase IRF-1 mRNA levels (Fujita et al. 1989 b) and that activation of the IFN-β gene requires the presence of IRF binding sites (Leblanc et al. 1990), also supported the view that IRF-1 is important in the transcriptional activation of the endogenous IFN-β gene. It was also demonstrated that cells transfected with a construct expressing sense IRF-1 mRNA produced significantly higher levels of IFN-β mRNA and protein than control cells, whereas cells expressing antisense IRF-1 mRNA produced little or no IFN-β mRNA and protein (Reis et al. 1992).
KeywordsToxicity Saccharide Tyrosine Tuberculosis Nitrite
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- Green SJ, Nacy CA, Schreiber RD, Granger DL, Crawford RM, Meltzer MS, Fortier AH (1993) Neutralization of gamma interferon and tumor necrosis factor alpha blocks in vivo synthesis of nitrogen oxides from L-arginine and protection against Francisella tularensis infection in Mycobacterium bovis BCG-treated mice. Infect Immun 61:689–698PubMedGoogle Scholar
- Kamijo R, Le J, Shapiro D, Havell EA, Huang S, Aguet M, Bosland M, Vilček J (1993a) Mice that lack the interferon-γ receptor have profoundly altered responses to infection with Bacillus Calmette-Guérin and subsequent challenge with lipopolysaccharide. J Exp Med 178:1435–1440PubMedCrossRefGoogle Scholar
- Pine R, Decker T, Kessler DS, Levy DE, Darnell JE Jr (1990) Purification and cloning of interferon-stimulated gene factor 2 (ISGF2): ISGF2 (IRF-1) can bind to the promoters of both β interferon- and interferon-stimulated genes but is not a primary transcriptional activator of either. Mol Cell Biol 10:2448–2457PubMedGoogle Scholar
- Pine R, Canova A, Schindler C (1994) Tyrosine phosphorylated p91 binds to a single element in the ISGF2/IRF-1 promoter to mediate induction by IFN-α and IFN-β, and is likely to autoregulate the p91 gene. EMBO J13:158–167Google Scholar
- Reis LFL, Ruffner H, Stark G, Aguet M, Weissmann C (1994) Mice devoid of interferon regulatory factor 1 (IRF-1) show normal expression of type I interferon genes. EMBO J13:4798–4806Google Scholar
- Taniguchi T, Fujita T, Yamada G, Miyamoto M, Harada H, Kimura Y, Maruyama M, Shibuya H (1989) Cytokine gene expression: regulation in the type I IFN and the IL-2 systems. In: Kawade Y, Kobayashi S (eds) The biology of the interferon system 1988. Kodansha, Tokyo, pp 3–10Google Scholar