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