論文 - 詳細
| RRC ID | 11804 |
|---|---|
| 著者 | Dogusan Z, García M, Flamez D, Alexopoulou L, Goldman M, Gysemans C, Mathieu C, Libert C, Eizirik DL, Rasschaert J. |
| タイトル | Double-stranded RNA induces pancreatic beta-cell apoptosis by activation of the toll-like receptor 3 and interferon regulatory factor 3 pathways. |
| ジャーナル | Diabetes |
| Abstract |
OBJECTIVE:Viral infections contribute to the pathogenesis of type 1 diabetes. Viruses, or viral products such as double-stranded RNA (dsRNA), affect pancreatic beta-cell survival and trigger autoimmunity by unknown mechanisms. We presently investigated the mediators and downstream effectors of dsRNA-induced beta-cell death. RESEARCH DESIGN AND METHODS:Primary rat beta-cells and islet cells from wild-type, toll-like receptor (TLR) 3, type I interferon receptor (IFNAR1), or interferon regulatory factor (IRF)-3 knockout mice were exposed to external dsRNA (external polyinosinic-polycytidylic acid [PICex]) or were transfected with dsRNA ([PICin]). RESULTS:TLR3 signaling mediated PICex-induced nuclear factor-kappaB (NF-kappaB) and IRF-3 activation and beta-cell apoptosis. PICin activated NF-kappaB and IRF-3 in a TLR3-independent manner, induced eukaryotic initiation factor 2 alpha phosphorylation, and triggered a massive production of interferon (IFN)-beta. This contributed to beta-cell death, as islet cells from IFNAR1(-/-) or IRF-3(-/-) mice were protected against PICin-induced apoptosis. CONCLUSIONS:PICex and PICin trigger beta-cell apoptosis via the TLR3 pathway or IRF-3 signaling, respectively. Execution of PICin-mediated apoptosis depends on autocrine effects of type I IFNs. |
| 巻・号 | 57(5) |
| ページ | 1236-45 |
| 公開日 | 2008-5-1 |
| DOI | 10.2337/db07-0844 |
| PII | db07-0844 |
| PMID | 18223009 |
| MeSH | Animals Cell Survival Cells, Cultured Insulin-Secreting Cells / cytology Insulin-Secreting Cells / physiology* Interferon Regulatory Factor-3 / physiology* Interferon-beta / biosynthesis Male Mice Mice, Inbred C57BL Mice, Knockout Poly I-C / pharmacology RNA, Double-Stranded / genetics* Rats Rats, Wistar Reverse Transcriptase Polymerase Chain Reaction Toll-Like Receptor 3 / deficiency Toll-Like Receptor 3 / genetics Toll-Like Receptor 3 / physiology* |
| IF | 7.72 |
| 引用数 | 74 |
| WOS 分野 | ENDOCRINOLOGY & METABOLISM |
| リソース情報 | |
| 実験動物マウス | RBRC00858 |