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Disruption of the γ-Interferon Signaling Pathway at the Level of Signal Transducer and Activator of Transcription-1 Prevents Immune Destruction of β-cells Conny A. Gysemans 1 , Laurence Ladrière 2 , Hanne Callewaert 1 , Joanne Rasschaert 2 , Daisy Flamez 2 , David E. Levy 3 , Patrick Matthys 4 , Décio L. Eizirik 2 and Chantal Mathieu 1 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 Address correspondence and reprint requests to Prof. Chantal Mathieu, LEGENDO, UZ Gasthuisberg O&N, Herestraat 49, B-3000 Leuven, Belgium. E-mail: chantal.mathieu{at}med.kuleuven.be Abstract β-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 β-cell apoptosis by studying the sensitivity of β-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)-γ (studied in combination with interleukin [IL]-1β)-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-1β and IFN-γ. Moreover, analysis of cell death in cytokine-exposed purified β-cells confirmed that protection was due to absence of STAT-1 in the β-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 3α 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-γ–mediated β-cell death and the subsequent development of immune-mediated diabetes. 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-κB, nuclear factor-κB SOCS, suppressor of cytokine signaling STAT, signal transducer and activator of transcription Footnotes C.A.G. and L.L. contributed equally to this study. Accepted May 3, 2005. Received February 2, 2005. DIABETES

Objective: To evaluate the incidence of hemolytic uremic syndrome (HUS) in Belgium and to determine the role of verocytotoxin‐producing Escherichia coli O 157:H7 and other serotypes (non‐O 157 VTEC). Methods: Twenty‐two centers, including the seven university hospitals, registered prospectively all cases of HUS; they collected clinical samples for isolation of VTEC strains and serum for detection of specific O‐lipopolysaccharide antibodies. Results: Forty‐seven cases of HUS (including five incomplete cases) were recorded. Three cases were seen in nonresidents. The incidence of complete HUS in Belgian residents was 4.3 cases/100 000 in children <5 years old, 1.8 cases/100 000 when all children <15 years were considered, and 0.42/100 000 when patients of all ages were taken into account. By combining bacteriologic and serologic results, evidence of VTEC infection was obtained in 64% of the patients, mainly but not exclusively in children with prodromal diarrhea. The 13 VTEC isolates belonged to serotypes O157:H7 (nine isolates), O26:H11, O121:H‐, O145:H‐ and O172:H‐ (one each) and all produced VT2 (+VT2vh‐a in three O157 strains) and were positive for the eaeA gene. Conclusions: The incidence rate found in this study and the high mortality and morbidity linked with this syndrome warrant further registration of pediatric and post‐diarrheic adult HUS cases and also examination of stools for both O157 and non‐O157 VTEC strains. For effective prevention of this disease, further study of the serotypes and accessory virulence factors associated with HUS is needed.