title: 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.
authors: Division of Cytokine Signaling, Department of Molecular Biology, Nagasaki University Graduate School of Biomedical Science, Nagasaki 852-8523, Japan.
authors: Hideki
authors: H
authors: Hayashi
authors: Tomoko
authors: T
authors: Kohno
authors: Kiyoshi
authors: K
authors: Yasui
authors: Hiroyuki
authors: H
authors: Murota
authors: Tohru
authors: T
authors: Kimura
authors: Gordon S
authors: GS
authors: Duncan
authors: Tomoki
authors: T
authors: Nakashima
authors: Kazuo
authors: K
authors: Yamamoto
authors: Ichiro
authors: I
authors: Katayama
authors: Yuhua
authors: Y
authors: Ma
authors: Koon Jiew
authors: KJ
authors: Chua
authors: Takashi
authors: T
authors: Suematsu
authors: Isao
authors: I
authors: Shimokawa
authors: Shizuo
authors: S
authors: Akira
authors: Yoshinao
authors: Y
authors: Kubo
authors: Tak Wah
authors: TW
authors: Mak
authors: Toshifumi
authors: T
authors: Matsuyama
mesh_terms: D061354:Acinar Cells / Q000378:metabolism; D000818:Animals; D002401:Cathepsin B / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D050836:Interferon Regulatory Factor-2 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010195:Pancreatitis / Q000235:genetics / Q000378:metabolism*; D011070:Poly I-C / Q000235:genetics; D029584:Prostatic Secretory Proteins / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000378:metabolism*; D014158:Transcription, Genetic; D014359:Trypsin Inhibitor, Kazal Pancreatic; D014361:Trypsin Inhibitors / Q000494:pharmacology; D014362:Trypsinogen / Q000235:genetics*
chemical_list: D006023:Glycoproteins; D050836:Interferon Regulatory Factor-2; D029584:Prostatic Secretory Proteins; D012330:RNA, Double-Stranded; C487134:Spink1 protein, mouse; D014361:Trypsin Inhibitors; D014359:Trypsin Inhibitor, Kazal Pancreatic; D014362:Trypsinogen; D002401:Cathepsin B; D011070:Poly I-C