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

Mice deficient for interferon regulatory factor ( Irf ) 2 ( Irf2 −/− mice) exhibit immunological abnormalities and cannot survive lymphocytic choriomeningitis virus infection. The pancreas of these animals is highly inflamed, a phenotype replicated by treatment with poly(I: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 IFNα/β receptor 1 ( Ifnar1 ) abolished poly(I:C)-induced pancreatitis but had no effect on the constitutive up-regulation of trypsinogen5 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 MDA5 , RIG-I , and TLR3 , which induced poly(I: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.