Islet-specific expression of IL-10 promotes diabetes in nonobese diabetic mice independent of Fas, perforin, TNF receptor-1, and TNF receptor-2 molecules

J Immunol. 2000 Sep 1;165(5):2841-9. doi: 10.4049/jimmunol.165.5.2841.

Abstract

Several death-signaling or death-inducing molecules have been implicated in beta cell destruction, including Fas, perforin, and TNFR-1. In this study, we examined the role of each death-signaling molecule in the IL-10-accelerated diabetes of nonobese diabetic (NOD) mice. Groups of IL-10-NOD mice, each deficient in either Fas, perforin, or TNFR-1 molecules, readily developed insulitis, and subsequently succumbed to diabetes with an accelerated kinetics and incidence similar to that observed in their wild-type or heterozygous IL-10-NOD littermates. Similarly, a TNFR-2 deficiency did not block accelerated diabetes in IL-10-NOD mice and spontaneous diabetes in NOD mice. These results demonstrate that pancreatic IL-10 promotes diabetes independent of Fas, perforin, TNFR-1, and TNFR-2 molecules. Subsequently, when cyclophosphamide, a diabetes-inducing agent, was injected into insulitis-free NOD. lpr/lpr mice, none of these mice developed insulitis or diabetes. Our data suggest that cyclophosphamide- but not IL-10-induced diabetes is Fas dependent. Overall, these findings provide evidence that pancreatic expression of IL-10 promotes diabetes independent of the major death pathways and provide impetus for identification of novel death pathways precipitating autoimmune destruction of insulin-producing beta cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / physiology*
  • Autoimmune Diseases / chemically induced
  • Autoimmune Diseases / etiology
  • Autoimmune Diseases / pathology
  • Cyclophosphamide / administration & dosage
  • Diabetes Mellitus, Type 1 / etiology
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Inflammation / genetics
  • Inflammation / immunology
  • Injections, Intravenous
  • Interleukin-10 / biosynthesis*
  • Interleukin-10 / physiology
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / immunology*
  • Islets of Langerhans / metabolism*
  • Islets of Langerhans / pathology
  • Male
  • Membrane Glycoproteins / deficiency
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred MRL lpr
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, Transgenic
  • Perforin
  • Pore Forming Cytotoxic Proteins
  • Receptors, Tumor Necrosis Factor / deficiency
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / physiology*
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • Spleen / immunology
  • Spleen / pathology
  • Spleen / transplantation
  • fas Receptor / genetics
  • fas Receptor / physiology*

Substances

  • Antigens, CD
  • Membrane Glycoproteins
  • Pore Forming Cytotoxic Proteins
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • fas Receptor
  • Perforin
  • Interleukin-10
  • Cyclophosphamide