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J. Biol. Chem., Vol. 280, Issue 40, 33984-33991, October 7, 2005

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Toll-like Receptor 3 and STAT-1 Contribute to Double-stranded RNA+ Interferon--induced Apoptosis in Primary Pancreatic -Cells^*

Joanne Rasschaert1, Laurence Ladrière, Maryse Urbain, Zeynep Dogusan, Bitty Katabua, Shintaro Sato, Shizuo Akira, Conny Gysemans¶, Chantal Mathieu¶, and Decio L. Eizirik

From the Laboratory of Experimental Medicine, Université Libre de Bruxelles, Route de Lennik, 808, CP 618, B-1070 Brussels, Belgium, the Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan, and the ^¶Laboratory of Experimental Medicine and Endocrinology, Katholieke Universiteit Leuven, Leuven 3000, Belgium

Viral infections and local production of cytokines probably contribute to the pathogenesis of Type 1 diabetes. The viral replicative intermediate double-stranded RNA (dsRNA, tested in the form of polyinosinic-polycytidylic acid, PIC), in combination with the cytokine interferon- (IFN-), triggers -cell apoptosis. We have previously observed by microarray analysis that PIC induces expression of several mRNAs encoding for genes downstream of Toll-like receptor 3 (TLR3) signaling pathway. In this report, we show that exposure of -cells to dsRNA in combination with IFN-, -, or - significantly increases apoptosis. Moreover, dsRNA induces TLR3 mRNA expression and activates NF-B and the IFN- promoter in a TRIF-dependent manner. dsRNA also induces an early (1 h) and sustained increase in IFN- mRNA expression, and blocking IFN- with a specific antibody partially prevents PIC plus IFN--induced -cell death. On the other hand, dsRNA plus IFN- does not induce apoptosis in INS-1E cells, and expression of TLR3 and type I IFNs mRNAs is not detected in these cells. Of note, disruption of the STAT-1 signaling pathway protects -cells against dsRNA plus IFN--induced -cell apoptosis. This study suggests that dsRNA plus IFN- triggers -cell apoptosis by two complementary pathways, namely TLR3-TRIF-NF-B and STAT-1.

Received for publication, February 28, 2005 , and in revised form, July 13, 2005.

^* This study was supported by grants from the EFSD/JDRF/Novo Nordisk Type 1 Diabetes Research Programme and the Fonds de la Recherche Scientifique Médicale, Belgium (convention 3.4514.03). This work has been conducted in collaboration with and supported by the JDRF Center for Prevention of -Cell Destruction in Europe (Grant 4-20002-457). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 32-2-555-6307; Fax: 32-2-555-6239; E-mail: jrasscha{at}ulb.ac.be.

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