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).