|Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2002: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
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
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