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

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

  • Other Ca2+-binding proteins
  • Other Cathepsin B
  • Other IPS-1
  • Other TRIF
  • 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.
  • identifier:Proceedings of the National Academy of Sciences of the United States of America, 108(46), pp.18766-18771; 2011
  • identifier:10916490
PublisherNational Academy of Sciences
Date Issued 2011-11-15
NIItypejournal article
Identifier URI
  • isIdenticalTo PMID 22042864
  • isIdenticalTo DOI
    • ISSN 0027-8424
    • Proceedings of the National Academy of Sciences of the United States of America
    108(46), 18766-18771