Characterization of dsRNA-induced pancreatitis model reveals the regulatory role of IFN regulatory factor 2 (Irf2) in trypsinogen5 gene transcription.
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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.
内容記述
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1116273108/-/DCSupplemental.
雑誌名
Proceedings of the National Academy of Sciences of the United States of America
巻
108
号
46
ページ
18766 - 18771
発行年
2011-11-15
ISSN
00278424
EISSN
10916490
書誌レコードID
AA10808769@@@AA12104563
PubMed番号
22042864
DOI
10.1073/pnas.1116273108
著者版フラグ
author
出版者
National Academy of Sciences
引用
Proceedings of the National Academy of Sciences of the United States of America, 108(46), pp.18766-18771; 2011
Characterization of dsRNA-induced pancreatitis model reveals the regulatory role of IFN regulatory factor 2 (Irf2) in trypsinogen5 gene transcription.
PNAS108_18766.pdf
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