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Department of Microbiology and Immunology, University of Maryland, Baltimore, MD 21201
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-
mRNA and circulating TNF- were significantly elevated in LPS-challenged IRF-2-/- mice, levels of IL-1, IL-12, and IFN-
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- 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
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- 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, IL-6, and IFN- 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.
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