Cuesta Natalia, Salkowski Cindy A, Thomas Karen E, Vogel Stefanie N
Department of Microbiology and Immunology, University of Maryland, Baltimore, MD 21201, USA.
J Immunol. 2003 Jun 1;170(11):5739-47. doi: 10.4049/jimmunol.170.11.5739.
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.
干扰素调节因子（IRFs）是一类转录因子，包括几个调节促炎和抗炎基因表达的成员。在注射脂多糖（LPS）后，对IRF-2发生靶向突变的小鼠（IRF-2(-/-)）进行了研究，以评估IRF-2在内毒素毒性调节中的重要性。IRF-2(-/-)小鼠对LPS诱导的致死性具有高度抗性。尽管在受到LPS攻击的IRF-2(-/-)小鼠中，肝脏肿瘤坏死因子-α（TNF-α）mRNA和循环TNF-α显著升高，但白细胞介素-1（IL-1）、IL-12、干扰素-γ（IFN-γ）mRNA和蛋白水平以及IL-6蛋白水平均显著低于受到LPS攻击的IRF-2(+/+)小鼠。IRF-2(-/-)小鼠对TNF-α攻击也比对照小鼠更具抗性，这与其对LPS敏感性降低一致，但未观察到肿瘤坏死因子受体（TNFRs）mRNA表达有显著差异。受到LPS攻击的IRF-2(-/-)小鼠的IL-12Rβ2 mRNA水平在1、6和8小时后有显著差异，表明IL-12减少和IL-12R表达改变均导致产生的IFN-γ减少。IRF-2基因敲除小鼠也未能维持LPS诱导的IRF-1和干扰素共有序列结合蛋白mRNA表达水平，这两种反式作用因子是IL-12转录所必需的，可能是由于IL-1β、IL-6和IFN-γ水平降低所致。在给予通常致死剂量的LPS 6小时后，对IRF-2(+/+)和IRF-2(-/-)小鼠的肝脏切片进行分析。IRF-2(-/-)小鼠的凋亡库普弗细胞数量比野生型小鼠更多，提示IRF-2具有新的抗凋亡作用。总体而言，这些发现揭示了IRF-2在内毒素毒性中的关键作用，并指出了IRF-2在细胞凋亡调节中以前未被认识的作用。
