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

Content Provider	PubMed Central
Author	Hayashi, Hideki Kohno, Tomoko Yasui, Kiyoshi Murota, Hiroyuki Kimura, Tohru Duncan, Gordon S. Nakashima, Tomoki Yamamoto, Kazuo Katayama, Ichiro Ma, Yuhua Chua, Koon Jiew Suematsu, Takashi Shimokawa, Isao Akira, Shizuo Kubo, Yoshinao Mak, Tak Wah Matsuyama, Toshifumi
Abstract	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.
Related Links	http://dx.doi.org/10.1073/pnas.1116273108
Ending Page	18771
Page Count	6
Starting Page	18766
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	46
Volume Number	108
Language	English
Publisher	National Academy of Sciences
Publisher Date	2011-11-15
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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