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

Diabetologia. 2001 May;44(5):567-74. doi: 10.1007/s001250051662.

Abstract

Aims/hypothesis: Disruption of the interferon-gamma (IFN-gamma) 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-gamma 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-gamma receptor knockout mice (IFN-gammaR-/-) 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-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 sensitivity to immune destruction of IRF-1-/- islets was observed when these islets were used as allografts. Islet graft survival rate of IFN-gammaR-/- 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 C57B1/6 controls (9.1 +/- 2.0 days vs 13.1 +/- 1.5 days, p < 0.003).

Conclusions/interpretation: These data indicate that IFN-gamma signal 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Crosses, Genetic
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Diabetes Mellitus, Experimental / immunology*
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Experimental / surgery
  • Graft Survival
  • Interferon Regulatory Factor-1
  • Interferon-gamma / genetics
  • Interleukin-1 / genetics
  • Interleukin-6 / genetics
  • Islets of Langerhans / immunology
  • Islets of Langerhans / pathology
  • Islets of Langerhans Transplantation*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Mice, Knockout
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase Type II
  • Phosphoproteins / deficiency
  • Phosphoproteins / genetics
  • Phosphoproteins / physiology*
  • Receptors, Interferon / deficiency
  • Receptors, Interferon / genetics
  • Receptors, Interferon / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transplantation, Homologous
  • Tumor Necrosis Factor-alpha / genetics

Substances

  • DNA-Binding Proteins
  • Interferon Regulatory Factor-1
  • Interleukin-1
  • Interleukin-6
  • Irf1 protein, mouse
  • Phosphoproteins
  • Receptors, Interferon
  • Tumor Necrosis Factor-alpha
  • interferon gamma receptor
  • Interferon-gamma
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse