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

IFN转录因子、IRF-1和IRF-2在急性肝损伤模型中的作用

基本信息

批准号：
10470060
负责人：
MATSUYAMA Toshifumi
金额：
$ 6.46万
依托单位：
Nagasaki University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10470060/
关键词：
cytokine interferon IRF transcription factor NF-kappaB

项目摘要

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.

本实验研究了干扰素调节因子（IRF-1、IRF-2）和干扰素相关细胞因子（TNF）在急性肝炎模型中的作用。我们发现，IRF-1缺陷型小鼠比对照组更容易死亡，当小鼠用LPS治疗后，痤疮丙酸杆菌引发。由于TNF和Fas配体表达水平在IRF-1缺陷小鼠中没有改变，因此建议涉及除Fas-Fas配体系统之外的途径。另一方面，TNF受体缺陷小鼠对刺激有抵抗力，表明TNF的重要性。有趣的是，CC趋化因子巨噬细胞炎性蛋白-3 α（MIP-3 α）在刺激后在肝脏中被诱导表达，并且该诱导明确依赖于TNF诱导的NF-κ B活化。由于MIP 3 α通过化学吸引T细胞启动炎症反应，因此MIP 3 α必须是肝损伤模型中的关键分子。已知IRF-1可被TNF或IFN诱导。我们发现IRF-1的启动子区含有一个新的TNF-反应元件，它结合NF-κ B。我们还证实了IRF-2缺陷小鼠胰腺腺泡细胞的异常成熟，并在注射poly（I）：poly（C）后发展为致死性胰腺炎。然而，肝脏似乎几乎没有损伤。这些结果表明IRF-2在胰腺发育和发病机制中的新作用，并首次证明病毒拟态是急性胰腺炎的病原体。