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Title
  • ja Characterization of dsRNA-induced pancreatitis model reveals the regulatory role of IFN regulatory factor 2 (Irf2) in trypsinogen5 gene transcription.
Creator
    • 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
Subject
  • Other Ca2+-binding proteins
  • Other Cathepsin B
  • Other IPS-1
  • Other TRIF
Description
  • Other 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.
  • Other This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1116273108/-/DCSupplemental.
  • Other identifier:Proceedings of the National Academy of Sciences of the United States of America, 108(46), pp.18766-18771; 2011
Publisher National Academy of Sciences
Date
    Created2020-12-22 , Issued2011-11-15
Language
  • eng
Resource Type journal article
Version Type AM
Identifier URI http://hdl.handle.net/10069/26998
Relation
  • isIdenticalTo PMID 22042864
  • isIdenticalTo DOI https://doi.org/10.1073/pnas.1116273108
Journal
    • ISSN 0027-8424
    • ISSN 1091-6490
      • Proceedings of the National Academy of Sciences of the United States of America 108(46), 18766-18771
File
Oaidate 2021-02-17