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


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.

SUBMITTER: Hayashi H 

PROVIDER: S-EPMC3219097 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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

Hayashi Hideki H   Kohno Tomoko T   Yasui Kiyoshi K   Murota Hiroyuki H   Kimura Tohru T   Duncan Gordon S GS   Nakashima Tomoki T   Yamamoto Kazuo K   Katayama Ichiro I   Ma Yuhua Y   Chua Koon Jiew KJ   Suematsu Takashi T   Shimokawa Isao I   Akira Shizuo S   Kubo Yoshinao Y   Mak Tak Wah TW   Matsuyama Toshifumi T  

Proceedings of the National Academy of Sciences of the United States of America 20111031 46


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) ab  ...[more]

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