Regulation of Lipopolysaccharide Sensitivity by IFN Regulatory Factor-2

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-alpha mRNA and circulating TNF-alpha were significantly elevated in LPS-challenged IRF-2(-/-) mice, levels of IL-1, IL-12, and IFN-gamma 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-alpha 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-12R beta 2 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-gamma 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-1 beta, IL-6, and IFN-gamma 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.