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

被引：16

作者：

Hayashi, Hideki ^{[7
]}

Kohno, Tomoko ^{[7
]}

Yasui, Kiyoshi ^{[7
]}

Murota, Hiroyuki ^{[5
]}

Kimura, Tohru ^{[6
]}

Duncan, Gordon S. ^{[1
]}

Nakashima, Tomoki ^{[2
]}

Yamamoto, Kazuo ^{[1
]}

Katayama, Ichiro ^{[5
]}

Ma, Yuhua ^{[7
]}

Chua, Koon Jiew ^{[7
]}

Suematsu, Takashi ^{[7
]}

Shimokawa, Isao ^{[8
]}

Akira, Shizuo ^{[4
]}

Kubo, Yoshinao ^{[7
]}

Mak, Tak Wah ^{[1
]}

Matsuyama, Toshifumi ^{[3
,7
]}

机构：

[1] Princess Margaret Hosp, Campbell Family Canc Res Inst, Toronto, ON M5G 2M9, Canada

[2] Tokyo Med & Dent Univ, Dept Cell Signaling, Tokyo 1138549, Japan

[3] Nagasaki Univ, Global Ctr Excellence Program, Nagasaki 8528523, Japan

[4] Osaka Univ, Dept Host Def, Microbial Dis Res Inst, Suita, Osaka 5650871, Japan

[5] Osaka Univ, Grad Sch Med, Dept Dermatol, Suita, Osaka 5650871, Japan

[6] Osaka Univ, Grad Sch Med, Dept Pathol, Suita, Osaka 5650871, Japan

[7] Nagasaki Univ, Grad Sch Biomed Sci, Div Cytokine Signaling, Dept Mol Biol & Immunol, Nagasaki 8528523, Japan

[8] Nagasaki Univ, Grad Sch Biomed Sci, Dept Invest Pathol, Nagasaki 8528523, Japan

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2011年 / 108卷 / 46期

关键词：

TRIF; IPS-1; Ca(2+)-binding proteins; cathepsin B; CATHEPSIN-B; ACINAR-CELLS; ADAPTER TRIF; ACTIVATION; INDUCTION; APOPTOSIS; DISEASE; MICE;

D O I：

10.1073/pnas.1116273108

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 IFN alpha/beta 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.

引用

页码：18766 / 18771

页数：6

共 33 条

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