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

TitleCharacterization of dsRNA-induced pancreatitis model reveals the regulatory role of IFN regulatory factor 2 (Irf2) in trypsinogen5 gene transcription
Authors
KeywordsTRIF
Ca -binding proteins 2+
IPS-1
Cathepsin B
Issue Date2011
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2011, v. 108, n. 46, p. 18766-18771 How to Cite?
AbstractMice 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.
Persistent Identifierhttp://hdl.handle.net/10722/292671
ISSN
2023 Impact Factor: 9.4
2023 SCImago Journal Rankings: 3.737
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorHayashi, Hideki-
dc.contributor.authorKohno, Tomoko-
dc.contributor.authorYasui, Kiyoshi-
dc.contributor.authorMurota, Hiroyuki-
dc.contributor.authorKimura, Tohru-
dc.contributor.authorDuncan, Gordon S.-
dc.contributor.authorNakashima, Tomoki-
dc.contributor.authorYamamoto, Kazuo-
dc.contributor.authorKatayama, Ichiro-
dc.contributor.authorMa, Yuhua-
dc.contributor.authorChua, Koon Jiew-
dc.contributor.authorSuematsu, Takashi-
dc.contributor.authorShimokawa, Isao-
dc.contributor.authorAkira, Shizuo-
dc.contributor.authorKubo, Yoshinao-
dc.contributor.authorMak, Tak Wah-
dc.contributor.authorMatsuyama, Toshifumi-
dc.date.accessioned2020-11-17T14:56:58Z-
dc.date.available2020-11-17T14:56:58Z-
dc.date.issued2011-
dc.identifier.citationProceedings of the National Academy of Sciences of the United States of America, 2011, v. 108, n. 46, p. 18766-18771-
dc.identifier.issn0027-8424-
dc.identifier.urihttp://hdl.handle.net/10722/292671-
dc.description.abstractMice 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.-
dc.languageeng-
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of America-
dc.subjectTRIF-
dc.subjectCa -binding proteins 2+-
dc.subjectIPS-1-
dc.subjectCathepsin B-
dc.titleCharacterization of dsRNA-induced pancreatitis model reveals the regulatory role of IFN regulatory factor 2 (Irf2) in trypsinogen5 gene transcription-
dc.typeArticle-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1073/pnas.1116273108-
dc.identifier.pmid22042864-
dc.identifier.pmcidPMC3219097-
dc.identifier.scopuseid_2-s2.0-81755186997-
dc.identifier.volume108-
dc.identifier.issue46-
dc.identifier.spage18766-
dc.identifier.epage18771-
dc.identifier.eissn1091-6490-
dc.identifier.isiWOS:000297008900047-
dc.identifier.f100013393972-
dc.identifier.issnl0027-8424-

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