Characterization of dsRNA-induced pancreatitis model reveals the regulatory role of IFN regulatory factor 2 (Irf2) in trypsinogen5 gene transcription

摘要

Mice deficient for interferon regulatory factor (Irf)2 (Irf2~(-/-) mice) exhibit immunological abnormalities and cannot survive lympho-cytic choriomeningitis virus infection. The pancreas of these animals is highly inflamed, a phenotype replicated by treatment with poly(l:C), a synthetic double-stranded RNA. Trypsinogen5 mRNA was constitutively up-regulated about 1,000-fold in Irf2~(-/-) mice compared with controls as assessed by quantitative RT-PCR. Further knockout of IFNa/p receptor 1{lfnar1) abolished poly(l:C)-induced pancreatitis but had no effect on the constitutive up-reg-ulation of trypsinogenS gene, indicating crucial type I IFN signaling to elicit the inflammation. Analysis of Ifnar1~(-/-) mice confirmed type I IFN-dependent transcriptional activation of dsRNA-sensing pattern recognition receptor genes MDAS, RIG-I, and TLR3, which induced poly(l:C)-dependent cell death in acinar cells in the absence of IRF2. We speculate that Trypsin5, the trypsinogen5 gene product, leaking from dead acinar cells triggers a chain reaction leading to lethal pancreatitis in Irf2~(-/-) mice because it is resistant to a major endogenous trypsin inhibitor, Spink3.