Molecular mechanism of acute pancreatitis provoked by double-stranded RNA

总之，这项研究的结果提供了证据，证明转录因子IRF-2是胰腺腺泡细胞发育和/或成熟所必需的，也是保护dsRNA诱导的细胞凋亡所必需的。后者提示，在缺乏IRF-2表达的情况下，胰腺腺泡细胞对病毒感染和PolyI：PolyC诱导的细胞凋亡变得敏感。以往的研究表明，IRF-2的抗凋亡作用是通过调节干扰素诱导的促凋亡基因的表达来实现的。然而，在缺乏IRF-2的胰腺腺泡细胞中，PolyC诱导这些基因的表达并没有明显改变，这表明除了这里所检测的干扰素诱导的促凋亡基因外，还有其他基因参与其中。临床上，10%的胰腺炎被诊断为特发性。虽然我们目前还不知道irf-2在胰腺中的表达是如何生理性下调的，但推测…是有趣的。更重要的是，一些特发性胰腺炎病例可能是由潜伏的病毒感染引起的，存在异常低浓度的IRF-2。有趣的是，人类免疫缺陷病毒(HIV)感染经常与胰腺炎相关，而HHV-8/KSHV是HIV相关Kaposi肉瘤的偶然因子，在开放阅读框K9编码病毒IRF(VIRF)-2。体外结合实验证实了重组vIRF-2与细胞内ERF-2、relA或p300的结合，并且vIRF-2对IRF-2具有显性的负活性。由于KSHV被认为可以感染胰腺，因此我们推测感染这种病毒的艾滋病患者胰腺中IRF-2的表达可能降低，因此在机会性病毒感染后容易发生凋亡诱导的胰腺炎。在我们的小鼠胰腺炎模型中，检测KSHV来源的vIRF-2可能参与的研究正在进行中。较少

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