RESUMEN
AIMS/HYPOTHESIS: Islet cell death is a key initiating and perpetuating event in type 1 diabetes and involves both immune-mediated and endogenous mechanisms. The epithelial pantetheinase vanin-1 is proinflammatory and cytoprotective via cysteamine release in some tissues. We investigated the impact of a vanin-1 deficiency on islet death and type 1 diabetes incidence. METHODS: Vanin-1-deficient mice were produced and tested in drug-induced and autoimmune diabetes models. The contribution of vanin-1 to islet survival versus immune responses was evaluated using lymphocyte transfer and islet culture experiments. RESULTS: The vanin-1/cysteamine pathway contributes to the protection of islet beta cells from streptozotocin-induced death in vitro and in vivo. Furthermore, vanin-1-deficient NOD mice showed a significant aggravation of diabetes, which depended upon loss of vanin-1 expression by host tissues. This increased islet fragility was accompanied by greater CD4+ insulitis without impairment of regulatory cells. Addition of cystamine, the product of pantetheinase activity, protected islets in vitro and compensated for vanin-1 deficiency in vivo. CONCLUSIONS/INTERPRETATION: This study unravels a major cytoprotective role of cysteamine for islet cells and suggests that modulation of pantetheinase activity may offer alternative strategies to maintain islet cell homeostasis.
Asunto(s)
Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patología , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Amidohidrolasas , Animales , Moléculas de Adhesión Celular/deficiencia , Muerte Celular/fisiología , Células Cultivadas , Cistamina/farmacología , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/prevención & control , Diabetes Mellitus Tipo 1/epidemiología , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Femenino , Proteínas Ligadas a GPI , Homeostasis/fisiología , Incidencia , Insulina/metabolismo , Estimación de Kaplan-Meier , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Ratones Mutantes , Linfocitos T Reguladores/patología , Células TH1/patologíaRESUMEN
A remarkable aspect of Dictyostelium development is that cells form evenly sized groups of approximately 2 x 10(4) cells. A secreted 450 kDa protein complex called counting factor (CF) regulates the number of cells per group. We find that CF regulates group size by repressing cell-cell adhesion. In both experiments and computer simulations, high levels of CF (and thus low adhesion) result in aggregation streams breaking up into small groups, while no CF (and thus high adhesion) results in no stream breakup and large groups. These results suggest that in Dictyostelium and possibly other systems a secreted factor regulating cell-cell adhesion can regulate the size of a group of cells.
