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Disruption of the -Interferon Signaling Pathway at the Level of Signal Transducer and Activator of Transcription-1 Prevents Immune Destruction of ß-cells

¹ Laboratory of Experimental Medicine and Endocrinology, UZ Gasthuisberg O&N, Katholieke Universiteit Leuven, Leuven, Belgium
² Laboratory of Experimental Medicine, Université Libre de Bruxelles, Brussels, Belgium
³ Department of Pathology and Kaplan Cancer Center, New York University School of Medicine, New York, New York
⁴ Laboratory of Immunobiology, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium

ß-Cells under immune attack are destroyed by the aberrant activation of key intracellular signaling cascades. The aim of the present study was to evaluate the contribution of the signal transducer and activator of transcription (STAT)-1 pathway for ß-cell apoptosis by studying the sensitivity of ß-cells from STAT-1 knockout (–/–) mice to immune-mediated cell death in vitro and in vivo. Whole islets from STAT-1^–/– mice were completely resistant to interferon (IFN)- (studied in combination with interleukin [IL]-1ß)-mediated cell death (92 ± 4% viable cells in STAT-1^–/– mice vs. 56 ± 3% viable cells in wild-type controls, P 0.001) and had preserved insulin release after exposure to IL-1ß and IFN-. Moreover, analysis of cell death in cytokine-exposed purified ß-cells confirmed that protection was due to absence of STAT-1 in the ß-cells themselves. Deficiency of STAT-1 in islets completely prevented cytokine-induced upregulation of IL-15, interferon inducible protein 10, and inducible nitric oxide synthase transcription but did not interfere with monocyte chemoattractant protein 1 and macrophage inflammatory protein 3 expression. In vivo, STAT-1^–/– mice were partially resistant to development of diabetes after multiple low-dose streptozotocin injections as reflected by mean blood glucose at 12 days after first injection (159 ± 28 vs. 283 ± 81 mg/dl in wild-type controls, P 0.05) and diabetes incidence at the end of the follow-up period (39 vs. 73% in wild-type controls, P 0.05). In conclusion, the present results indicate that STAT-1 is a crucial transcription factor in the process of IFN-–mediated ß-cell death and the subsequent development of immune-mediated diabetes.

Abbreviations: ELISA, enzyme-linked immunosorbent assay; FACS, fluorescence-activated cell sorter; IFN, interferon; IL, interleukin; iNOS, inducible nitric oxide synthase; IP, interferon-inducible protein; IPGTT, intraperitoneal glucose tolerance test; IRF, interferon regulatory factor; JAK, janus kinase; MIP, macrophage inflammatory protein; MLDS, multiple low-dose streptozotocin; NF-B, nuclear factor-B; SOCS, suppressor of cytokine signaling; STAT, signal transducer and activator of transcription

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