{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T16:33:04Z","timestamp":1781109184011,"version":"3.54.1"},"reference-count":26,"publisher":"National Academy of Sciences","issue":"46","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2011,11,15]]},"abstract":"<jats:p>\n                    Mice deficient for\n                    <jats:italic>interferon regulatory factor<\/jats:italic>\n                    (\n                    <jats:italic>Irf<\/jats:italic>\n                    )\n                    <jats:italic>2<\/jats:italic>\n                    (\n                    <jats:italic>Irf2<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    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\n                    <jats:italic>Irf2<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice compared with controls as assessed by quantitative RT-PCR. Further knockout of\n                    <jats:italic>IFN\u03b1\/\u03b2 receptor 1<\/jats:italic>\n                    (\n                    <jats:italic>Ifnar1<\/jats:italic>\n                    ) abolished poly(I:C)-induced pancreatitis but had no effect on the constitutive up-regulation of\n                    <jats:italic>trypsinogen5<\/jats:italic>\n                    gene, indicating crucial type I IFN signaling to elicit the inflammation. Analysis of\n                    <jats:italic>Ifnar1<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice confirmed type I IFN-dependent transcriptional activation of dsRNA-sensing pattern recognition receptor genes\n                    <jats:italic>MDA5<\/jats:italic>\n                    ,\n                    <jats:italic>RIG-I<\/jats:italic>\n                    , and\n                    <jats:italic>TLR3<\/jats:italic>\n                    , which induced poly(I:C)-dependent cell death in acinar cells in the absence of IRF2. We speculate that Trypsin5, the\n                    <jats:italic>trypsinogen5<\/jats:italic>\n                    gene product, leaking from dead acinar cells triggers a chain reaction leading to lethal pancreatitis in\n                    <jats:italic>Irf2<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice because it is resistant to a major endogenous trypsin inhibitor, Spink3.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1116273108","type":"journal-article","created":{"date-parts":[[2011,11,1]],"date-time":"2011-11-01T00:21:08Z","timestamp":1320106868000},"page":"18766-18771","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":18,"title":["Characterization of dsRNA-induced pancreatitis model reveals the regulatory role of\n                    <i>IFN regulatory factor 2<\/i>\n                    (\n                    <i>Irf2<\/i>\n                    ) in\n                    <i>trypsinogen5<\/i>\n                    gene transcription"],"prefix":"10.1073","volume":"108","author":[{"given":"Hideki","family":"Hayashi","sequence":"first","affiliation":[{"name":"Division of Cytokine Signaling, Department of Molecular Biology and Immunology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoko","family":"Kohno","sequence":"additional","affiliation":[{"name":"Division of Cytokine Signaling, Department of Molecular Biology and Immunology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiyoshi","family":"Yasui","sequence":"additional","affiliation":[{"name":"Division of Cytokine Signaling, Department of Molecular Biology and Immunology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Murota","sequence":"additional","affiliation":[{"name":"Dermatology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tohru","family":"Kimura","sequence":"additional","affiliation":[{"name":"Pathology, Graduate School of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordon S.","family":"Duncan","sequence":"additional","affiliation":[{"name":"Campbell Family Cancer Research Institute, Princess Margaret Hospital, Toronto, ON, Canada M5G 2M9;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoki","family":"Nakashima","sequence":"additional","affiliation":[{"name":"Department of Cell Signaling, Tokyo Medical and Dental University, Tokyo 113-8549, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuo","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Campbell Family Cancer Research Institute, Princess Margaret Hospital, Toronto, ON, Canada M5G 2M9;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ichiro","family":"Katayama","sequence":"additional","affiliation":[{"name":"Dermatology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhua","family":"Ma","sequence":"additional","affiliation":[{"name":"Division of Cytokine Signaling, Department of Molecular Biology and Immunology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koon Jiew","family":"Chua","sequence":"additional","affiliation":[{"name":"Division of Cytokine Signaling, Department of Molecular Biology and Immunology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Suematsu","sequence":"additional","affiliation":[{"name":"Division of Cytokine Signaling, Department of Molecular Biology and Immunology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isao","family":"Shimokawa","sequence":"additional","affiliation":[{"name":"Department of Investigative Pathology, Nagasaki University Graduate School of Biomedical Science, Nagasaki 852-8523, Japan; Departments of"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shizuo","family":"Akira","sequence":"additional","affiliation":[{"name":"Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinao","family":"Kubo","sequence":"additional","affiliation":[{"name":"Division of Cytokine Signaling, Department of Molecular Biology and Immunology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tak Wah","family":"Mak","sequence":"additional","affiliation":[{"name":"Campbell Family Cancer Research Institute, Princess Margaret Hospital, Toronto, ON, Canada M5G 2M9;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshifumi","family":"Matsuyama","sequence":"additional","affiliation":[{"name":"Division of Cytokine Signaling, Department of Molecular Biology and Immunology and"},{"name":"Global Center of Excellence Program, Nagasaki University, Nagasaki 852-8523, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2011,10,31]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-009-0804-6"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.05.006"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(05)80086-8"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)00064-9"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00432156"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2011.05.051"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1661"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.24.11284"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1087262"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genom-082908-150009"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.med.041608.121416"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2010.07.002"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/msi166"},{"key":"e_1_3_3_14_2","first-page":"293","article-title":"Possible lysosomal activation of pancreatic zymogens. 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