The regulation of the cytokine gene expression in cell growth and differentiation

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Two structurally related transcription factors, IRF-1 and IRF-2 were originally identified as regulators of the interferon (IFN) system. It has been shown that IRF-1 functions as an activator for the type I IFN genes and some IFN-inducible genes, whereas IRF-2 represses the effect of IRF-1 by competing for binding to the same DNA sequence elements (IRF-E_8). We demonstrated a role for IRF-1 as a tumor suppressor ; overexpression of the repressor IRF-2 in NIH3T3 cells causes cell transformation and this cell transformation is suppressed by concomitant overexpression of the activator IRF-1. To examine further the role of IRF-1 and IRF-2 in vivo, we genereted mice with a null mutation in the IRF-1 gene or IRF-2 gene by gene targetting. We demonstrate that (i) infection with BCG was more severe in IRF-1^<-/-> mice than in wild-type mice ; (ii) the inhibition of encephalimyocarditis virus (EMCV) replication by IFN was impared in cells from IRF-1^<-/-> mice and these mice were less resistant than wild-type mice to EMCV infection ; (iii) primary embryonic fibroblasts (EFs) with a null mutation in the IRF-1 gene (IRF-1^<-/-> mice) are susceptible to transformation by an activated form of c-Ha-ras, a property also seen in the EFs from p53^<-/-> mice, but not in wild-type EFs. Thus, IRF-1 contributes to antibacterial, antiviral, and antitumor functions. The human IRF-1 gene has been mapped to 5q31.1. It has been demonstrated that one or both human IRF-1 alleles were deleted in MDS and leukemia chracterrized by 5q abberations. We also found that the accelerated exon skipping of human IRF-1 gene may cause the inactivation of IRF-1 and thereby contribute to the development of human hematopoietic malignancies.