Abstract
Aims/hypothesis. Disruption of the interferon-gamma (IFN-γ) signalling pathway at the level of interferon regulatory factor-1 (IRF-1) protects islets against cytokine-induced nitric oxide production and cell death in vitro. The aim of this study was to investigate the effects of a global disruption of IFN-γ signalling, or a selective disruption of IRF-1, on beta-cell sensitivity to in vivo immune destruction. Methods. In a first set of experiments, IFN-γ receptor knockout mice (IFN-γR-/-) and interferon regulatory factor-1 knockout mice (IRF-1-/-) were rendered diabetic by injections of 50 mg streptozotocin i. p. on 5 consecutive days (MLDSTZ). Results. Whereas no difference in sensitivity to MLDSTZ-induced diabetes could be observed between IFN-γR-/- mice and their 129/Sv/Ev controls (50 % vs 55 %, NS), there was an increased incidence of diabetes in IRF-1-/- mice (100 % vs 67 % in C57Bl/6 mice, p < 0.05). A similar increased sensitivity to immune destruction of IRF-1-/- islets was observed when these islets were used as allografts. Islet graft survival rate of IFN-γR-/- and 129/Sv/Ev islets, when transplanted in alloxan-diabetic BALB/c recipients, was comparable (12.0 ± 1.9 days vs 12.9 ± 2.3 days, NS). Allograft rejection, however, of IRF-1-/- islets by BALB/c recipients occurred more rapidly than following transplantation to their C57Bl/6 controls (9.1 ± 2.0 days vs 13.1 ± 1.5 days, p < 0.003). Conclusions/interpretation. These data indicate that IFN-γ signal transduction at the beta-cell level is not essential for immune beta-cell destruction in vivo. Moreover, disruption of the IRF-1 gene in pancreatic islets increases susceptibility to beta-cell killing, suggesting that IRF-1 might be necessary for the expression of putative beta-cell “defence and/or repair” genes. [Diabetologia (2001) 44: 567–574]
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Received: 13 September 2000 and in revised form: 18 January 2001
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Gysemans, C., Pavlovic, D., Bouillon, R. et al. Dual role of interferon-γ signalling pathway in sensitivity of pancreatic beta cells to immune destruction. Diabetologia 44, 567–574 (2001). https://doi.org/10.1007/s001250051662
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DOI: https://doi.org/10.1007/s001250051662