Role of IFN transcription factors, IRF-1, and IRF-2 in acute hepatic injury model

探讨干扰素调节因子IRF-1、IRF-2、干扰素相关细胞因子、肿瘤坏死因子在急性肝炎模型中的作用。我们发现IRF-1缺陷小鼠比对照组更容易死亡，在P.ACNES免疫后用脂多糖处理小鼠。由于IRF-1基因缺陷小鼠肿瘤坏死因子和Fas配体的表达水平没有改变，提示可能存在Fas-Fas配体系统以外的其他途径参与。另一方面，肿瘤坏死因子受体缺陷小鼠对刺激具有抵抗力，表明肿瘤坏死因子的重要性。有趣的是，CC趋化因子巨噬细胞炎性蛋白-3α(MIP-3α)在刺激后在肝脏中被诱导表达，并且这种诱导肯定依赖于肿瘤坏死因子诱导的核因子-kappaB的激活。由于MIP3α通过趋化T细胞启动炎症反应，因此在肝损伤模型中MIP3α必然是关键分子。IRF-1已知是由肿瘤坏死因子或干扰素诱导的。我们发现IRF-1的启动子区域含有一个新的肿瘤坏死因子反应元件，它与核因子-kappaB结合。这一因素也归因于对IFN的反应性。我们还证明了IRF-2缺陷小鼠胰腺腺泡细胞的异常成熟，并在PolyI：Poly(C)注射后发展为致死性胰腺炎。然而，肝脏似乎几乎没有受损。这些结果表明，IRF-2在胰腺的发育和发病机制中发挥了新的作用，并且首次发现病毒模仿是急性胰腺炎的病原体。

The role of Interferon Regulatory Factors, IRF-1, and IRF-2, and IFN-related cytokine, TNF in acute hepatitis model was studied. We found that IRF-1 deficient mice were more liable to die than the control, when mice treated with LPS following p.acnes priming. As the level of TNF and Fas ligand expression was not changed in the IRF-1 deficient mice, involvement of a pathway other than Fas-Fas ligand system is suggested. On the other hand, TNF receptor deficient mice were resistant to the stimulation, indicating the importance of TNF. Interestingly, CC chemokine Macrophage inflammatory protein-3alpha (MIP-3alpha), was induced to express in the liver after the stimulation, and that the induction was definitely dependent on the NF-kappaB activation induced by TNF. Since MIP3 alpha initiates the inflammatory reactions by chemoattracting T cells, MIP3 alpha must be critical molecule in the hepatic injury model. IRF-1 has ben know to be induced by TNF or IFN. We found that the promoter region of the IRF-1 contains a novel TNF-responsive element, which binds NF-kappaB. This element also attributable to the responsiveness to IFN.We also demonstrate that mice IRF-2 deficient mice exhibited abnormal maturation of pancreatic acinar cells, and developed lethal pancreatitis after poly(I) : poly(C) injection. However, the liver seemed almost free of damage. These results indicate the novel role of IRF-2 in development and pathogenesis of pancreas, and for the first time that viral mimicry is a causative agent to produce acute pancreatits.