Role of the mitochondria in immune-mediated apoptotic death of the human pancreatic ? cell line ?Lox5.

ABSTRACT: Mitochondria are indispensable in the life and death of many types of eukaryotic cells. In pancreatic beta cells, mitochondria play an essential role in the secretion of insulin, a hormone that regulates blood glucose levels. Unregulated blood glucose is a hallmark symptom of diabetes. The onset of Type 1 diabetes is preceded by autoimmune-mediated destruction of beta cells. However, the exact role of mitochondria has not been assessed in beta cell death. In this study, we examine the role of mitochondria in both Fas- and proinflammatory cytokine-mediated destruction of the human beta cell line, ?Lox5. IFN? primed ?Lox5 cells for apoptosis by elevating cell surface Fas. Consequently, ?Lox5 cells were killed by caspase-dependent apoptosis by agonistic activation of Fas, but only after priming with IFN?. This beta cell line undergoes both apoptotic and necrotic cell death after incubation with the combination of the proinflammatory cytokines IFN? and TNF?. Additionally, both caspase-dependent and -independent mechanisms that require proper mitochondrial function are involved. Mitochondrial contributions to ?Lox5 cell death were analyzed using mitochondrial DNA (mtDNA) depleted ?Lox5 cells, or ?Lox5 ?(0) cells. ?Lox5 ?(0) cells are not sensitive to IFN? and TNF? killing, indicating a direct role for the mitochondria in cytokine-induced cell death of the parental cell line. However, ?Lox5 ?(0) cells are susceptible to Fas killing, implicating caspase-dependent extrinsic apoptotic death is the mechanism by which these human beta cells die after Fas ligation. These data support the hypothesis that immune mediators kill ?Lox5 cells by both mitochondrial-dependent intrinsic and caspase-dependent extrinsic pathways.

SUBMITTER: Lightfoot YL 

PROVIDER: S-EPMC3124469 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature