title: Islet-specific expression of IL-10 promotes diabetes in nonobese diabetic mice independent of Fas, perforin, TNF receptor-1, and TNF receptor-2 molecules.
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.
authors.affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: B
authors.initials: B
authors.lastname: Balasa
authors.forename: K
authors.initials: K
authors.lastname: Van Gunst
authors.forename: N
authors.initials: N
authors.lastname: Jung
authors.forename: D
authors.initials: D
authors.lastname: Balakrishna
authors.forename: P
authors.initials: P
authors.lastname: Santamaria
authors.forename: T
authors.initials: T
authors.lastname: Hanafusa
authors.forename: N
authors.initials: N
authors.lastname: Itoh
authors.forename: N
authors.initials: N
authors.lastname: Sarvetnick
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000209:etiology / Q000473:pathology; D003520:Cyclophosphamide / Q000008:administration & dosage; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D007275:Injections, Intravenous; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000502:physiology; D007515:Islets of Langerhans / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008822:Mice, Transgenic; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D013154:Spleen / Q000276:immunology / Q000473:pathology / Q000637:transplantation; D019014:fas Receptor / Q000235:genetics / Q000502:physiology*
chemical_list: D015703:Antigens, CD; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D019014:fas Receptor; D054353:Perforin; D016753:Interleukin-10; D003520:Cyclophosphamide