Molecular mechanism of acute pancreatitis provoked by double-stranded RNA

双链RNA诱发急性胰腺炎的分子机制

• 批准号: 13670530
• 负责人: MATSUYAMA Toshifumi
• 金额: $ 2.24万
• 依托单位: Nagasaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670530/
• 关键词: interferon; IRF-2; gene targeted mouse; pancreatits; ddI; AIDS; IRF; ウイルス感染

Collectively, the results of this study provide evidence that the transcription factor IRF-2 is required by pancreatic acinar cells for both their development and/or maturation, and in protection against dsRNA-induced apoptosis. The latter implies that in the absence of IRF-2 expression, pancreatic acinar cells become susceptible to apoptosis induced by virus infections as well as by poly(I):polyc. Previous studies have shown that the anti-apoptotic effect of IRF-2 is mediated through the regulation of expression of IFN-inducible pro-apoptotic genes. However, the induction of the expression of these genes by poly(I):polyc was not significantly altered in pancreatic acinar cells lacking IRF-2, suggesting that genes other than the IFN-inducible pro-apoptotic genes examined here are involved.Clinically, 10% of pancreatitis is diagnosed as idiopathic. Although we do not know at present how IRF-2-expression may be physiologically downregulated in the pancreas, it is interesting to speculate … More that some cases of idiopathic pancreatitis might be caused by latent viral infections in the presence of abnormally low concentrations of IRF-2. Intriguingly, human immunodeficiency virus (HIV) infection has often been associated with pancreatitis, and herpes virus 8/Kaposi sarcoma-associated herpes virus (HHV-8/KSHV), the casual factor in HIV-associated Kaposi sarcoma, encodes viral IRF (vIRF)-2 in open reading frame K9. An in vitro binding assay confirmed the association between recombinant vIRF-2 and cellular ERF-2, RelA, or p300, and vIRF-2 is proposed to have a dominant negative activity on IRF-2. Because KSHV has been suggested to infect the pancreas, we therefore hypothesize that it is possible that AIDS patients infected with this virus exhibit decreased IRF-2 expression in the pancreas and are therefore prone to apoptosis-induced pancreatitis after opportunistic virus infections. Study to examine in our murine model pancreatits the possible involvement of vIRF-2 derived from KSHV is underway. Less

总的来说，这项研究的结果提供了证据，转录因子IRF-2是所需的胰腺腺泡细胞的发展和/或成熟，并在保护对dsRNA诱导的细胞凋亡。后者意味着，在IRF-2表达的情况下，胰腺腺泡细胞变得对病毒感染以及poly（I）：polyc诱导的细胞凋亡敏感。先前的研究表明，IRF-2的抗凋亡作用是通过调节IFN诱导的促凋亡基因的表达来介导的。然而，在缺乏IRF-2的胰腺腺泡细胞中，poly（I）：polyc对这些基因表达的诱导没有显著改变，这表明除了IFN诱导的促凋亡基因之外的基因也参与其中。虽然我们目前还不知道IRF-2表达在胰腺中是如何生理性下调的，但有趣的是推测 ...更多信息 一些特发性胰腺炎病例可能是在IRF-2浓度异常低的情况下由潜伏性病毒感染引起的。有趣的是，人类免疫缺陷病毒（HIV）感染通常与胰腺炎相关，而疱疹病毒8/卡波西肉瘤相关疱疹病毒（HHV-8/KSHV）是HIV相关卡波西肉瘤中的偶然因子，在开放阅读框K9中编码病毒IRF（vIRF）-2。体外结合试验证实了重组vIRF-2与细胞ERF-2、RelA或p300之间的关联，并且vIRF-2对IRF-2具有显性负活性。由于KSHV已被建议感染胰腺，因此，我们假设，这是可能的，艾滋病患者感染这种病毒表现出减少IRF-2表达的胰腺，因此，易于发病诱导胰腺炎后，机会性病毒感染。在我们的小鼠胰腺炎模型中检测来源于KSHV的vIRF-2的可能参与的研究正在进行中。少

项目成果

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Sugita S, Kohno T, Yamamoto K, Imaizumi Y, Nakajima H, Ishimaru T, Matsuyama T: "Induction of macrophage-inflammatory protein-3alpha gene expression by TNF-dependent NF-kappaB activation"J Immunol.. 168. 5621-5628 (2002)

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Watanabe, T. Kakakawa, K、Ohata, S、Kitakawa, D.、Nishitai, G. 等人：“SEK1/MKK4 介导的 SAPK/JNK 信号通过不同于 NF-kB 的途径参与胚胎肝母细胞增殖。

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Imaizumi Y、Murota H、Kanda S、Hishikawa Y、Koji T 等人：“c-Met 原癌基因的表达及其可能参与成人 T 细胞白血病的肝脏侵袭”Clin Cancer Res. 9。

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