Regulation of Lipopolysaccharide Sensitivity by IFN Regulatory Factor-2

Abstract

IFN regulatory factors (IRFs) are a family of transcription factors and include several members that regulate expression of pro- and anti-inflammatory genes. Mice with a targeted mutation in IRF-2 (IRF-2−/−) were studied after injection of LPS to evaluate the importance of IRF-2 in the regulation of endotoxicity. IRF-2−/− mice were highly refractory to LPS-induced lethality. Although hepatic TNF-α mRNA and circulating TNF-α were significantly elevated in LPS-challenged IRF-2−/− mice, levels of IL-1, IL-12, and IFN-γ mRNA and protein, as well as IL-6 protein, were significantly lower than levels seen in LPS-challenged IRF-2+/+ mice. IRF-2−/− mice were also more refractory to TNF-α challenge than were control mice, which was consistent with their diminished sensitivity to LPS, yet no significant difference in the mRNA expression of TNFRs was observed. IL-12Rβ2 mRNA levels from LPS-challenged IRF-2−/− mice were significantly different after 1, 6, and 8 h, suggesting that both diminished IL-12 and altered IL-12R expression contribute to the paucity of IFN-γ produced. IRF-2 knockout mice also failed to sustain LPS-inducible levels of IRF-1 and IFN consensus sequence binding protein mRNA expression, two transacting factors required for IL-12 transcription, perhaps as a result of diminished IL-1β, IL-6, and IFN-γ levels. Liver sections from IRF-2+/+ and IRF-2−/− mice were analyzed 6 h after a typically lethal injection of LPS. IRF-2−/− mice exhibited greater numbers of apoptotic Kupffer cells than did wild-type mice, suggesting a novel anti-apoptotic role for IRF-2. Collectively, these findings reveal a critical role for IRF-2 in endotoxicity, and point to a previously unappreciated role for IRF-2 in the regulation of apoptosis.

Interferon regulatory factor-2 in orange-spotted grouper (Epinephelus coioides): Gene, inductive expression pattern and subcellular localization

“…The effective expression of IFN and IFN-induced genes could promote expression of IRF-2 (Cha and Deisseroth, 1994), so the increased expression of IRF-2 would keep the antiviral state in an elaborate way to prevent the host defense system from overreacting (Barnes et al, 2002a). Studies in mice with a targeted mutation in IRF-2 showed that IRF-2 knockout mice were highly refractory to LPS-induced lethality and the levels of IL-1, IL-6, IL-12, and IFN-γ mRNA or protein were significantly lower than levels seen in LPS-challenged wild-type mice (Cuesta et al, 2003). From these results, IRF-2 is believed to have a key role in LPS-induced signaling pathway.…”

“…IRF-2 is a critical transacting factor that regulates in vivo responses to LPS and is a potential oncogene (Harada et al, 1993). IRF-2 also has an unexpected role in the regulation of apoptosis and cell growth (Cuesta et al, 2003). Due to the significant differences between mammals and fish, much effort has been made to study fish IRF family in recent years, and a few members have been reported, such as IRF-1, IRF-2, IRF-3 and IRF-7 (Holland et al, 2008;Kileng et al, 2009;Caipang et al, 2009;Jia and Guo, 2008;Sun et al, 2006;Collet et al, 2003;Zhang et al, 2003).…”

IFN Regulatory Factor-2 Regulates Macrophage Apoptosis through a STAT1/3- and Caspase-1-Dependent Mechanism

“…We have shown previously that IRF-2 Ϫ/Ϫ Kupffer cells exhibit an aberrantly high apoptotic response both basally and after LPS or TNF-␣ challenge in vivo (34). Thus, we hypothesized that this dysregulation in apoptosis might be a general feature for macrophages deficient in the transcription factor IRF-2.…”

“…The breeding pairs for this colony were a gift from G. Splitter (University of Wisconsin, Madison, WI). Mice were bred, as described previously (34), and each animal was genotyped by PCR. Six-to 8-wk-old mice were used in all experiments.…”

“…IRF-1 regulates DNA damage-induced cell cycle arrest (29,30) and is involved in the regulation of apoptosis in several cell types (31)(32)(33). We suggested a role for IRF-2 in apoptosis after detecting greater numbers of apoptotic Kupffer cells in the livers of IRF-2 Ϫ/Ϫ mice when compared with wild-type littermates (34). Recently, the absence of IRF-2 has been shown to cause premature apoptosis of NK cells (35); however, the mechanism(s) by which IRF-2 regulates apoptosis is unknown.…”