Role of IFN regulatory factor 5 transcription factor in antiviral immunity and tumor suppression

Abstract

Host defense consists of two main aspects, namely, immune response to invading pathogens and suppression of tumor development. A family of transcription factors, IFN regulatory factors (IRFs), has recently gained much attention in terms of its critical role in linking these two aspects of host defense, wherein IRF5 was previously shown to play a critical role in the induction of proinflammatory cytokines by activation of Toll-like receptors. In the present study, using IRF5 gene-targeted mice (Irf5 ؊/؊ mice), we demonstrate another facet of the IRF5 function in the regulation of immune response and tumor suppression. We show that IRF5 is critical for antiviral immunity by showing that Irf5 ؊/؊ mice are highly vulnerable to viral infections, accompanied by a decrease in type I IFN induction in the sera. Furthermore, we show that Irf5 ؊/؊ fibroblasts are resistant to apoptosis upon viral infection, resulting in an enhanced viral propagation. Finally, we provide evidence that IRF5 is critical for the induction of apoptosis, but not in cell cycle arrest, in response to DNA damage and that IRF5 functions as a tumor suppressor by acting on a pathway that may be distinct from that for p53. These results, together with the dual regulation of IRF5 gene expression by IFN signaling and p53, may provide a new link in the transcriptional network underlying antiviral immunity and tumor suppression.A n efficient and regulated cellular response is central to host defense, and it is coordinated by a genetic regulatory network in which a given transcription factor controls the expression of a set of diverse target genes depending on the cell type and/or the nature of cellular stimuli. Signaling in the immune system elicited by infection with viruses or bacteria usually leads to the production of type I IFN and inflammatory cytokines, resulting in the elimination of these pathogens (1, 2). Yet another important aspect of immune signal is the induction of apoptosis, which may be termed an altruistic suicide, which inhibits the further spread of infectious pathogens (3). This apoptotic response is highly similar to the response to genotoxic agents, such as ionizing radiation and certain anticancer drugs, which also induce cellular apoptosis, that is, one of the hallmarks of tumor suppression (4, 5). Indeed, recent studies have expanded the concept of a close relationship between the immune signaling system and oncogenesis (6, 7).IFN regulatory factor (IRF) family members have been implicated as critical transcription factors that sense various environmental stresses and induce various genes required for an adequate cellular response (8-12). The first family member to be characterized was IRF1, which plays a critical role in the induction of both antiviral immunity and apoptosis of cells exposed to DNA-damaging agents (13,14). Indeed, IRF1 cooperates with the tumor suppressor p53 to induce cell cycle arrest through the induction of p21 WAF1/Cip1 , and IRF1 induces apoptosis of cells expressing an oncogene. In addition, IRF8 (also kno...

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