Dual role of interferon-gamma signalling pathway in sensitivity of pancreatic beta cells to immune destruction

Aims/hypothesis. Disruption of the interferon-gamma (IFN-gamma) signalling pathway at the level of interferon regulatory factor-1 (IRF-1) protects isl ets against cytokine-incluced nitric oxide production and cell death in vit ro. The aim of this study was to investigate the effects of a global disrup tion of IFN-gamma signalling, or a selective disruption of IRF-1, on beta-c ell sensitivity to in vivo immune destruction. Methods. In a first set of experiments, IFN-gamma receptor knockout mice (I FN-gammaR(-/-)) and interferon regulatory factor-1 knockout mice (IRF-1(-/- )) were rendered diabetic by injections of 50 mg streptozotocin i.p. on 5 c onsecutive days (MLDSTZ). Results. Whereas no difference in sensitivity to MLDSTZ-induced diabetes co uld be observed between IFN-gammaR(-/-) 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 C57B1/6 mice, p < 0.05). A similar increased sensi tivity to immune destruction of IRF-1(-/-) islets was observed when these i slets were used as allografts. Islet graft survival rate of IFN-<gamma>R-/- and 129/Sv/Ev islets, when transplanted in alloxan-diabetic BALB/c recipie nts. was comparable (12.0 +/- 1.9 days vs 12.9 +/- 2.3 da)is, NS). Allograf t rejection, however, of IRF-1(-/-) islets by BALB/c recipients occurred mo re 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-<gamma> signal tra nsduction at the beta-cell level is not essential for immune beta-cell dest ruction in vive. Moreover, disruption of the IRF-1 gene in pancreatic islet s increases susceptibility to beta-cell killing, suggesting that IRF-1 migh t be necessary for the expression of putative beta-cell "defence and/or rep air" genes.