Cross-talk between phosphatidylinositol 3-kinase/AKT and c-jun NH2-terminal kinase mediates survival of isolated human islets

Endocrinology
R AikinLawrence Rosenberg

Abstract

Therapeutic strategies aimed at the inhibition of specific cell death mechanisms may increase islet yield and improve cell viability and function after routine isolation. The aim of the current study was to explore the possibility of AKT-JNK cross-talk in islets after isolation and the relevance of c-jun NH2-terminal kinases (JNK) suppression on islet survival. After routine isolation, increased AKT activity correlated with suppression of JNK activation, suggesting that they may be related events. Indeed, the increase in AKT activation after isolation correlated with suppression of apoptosis signal-regulating kinase 1 (ASK1), a kinase acting upstream of JNK, by phosphorylation at Ser83. We therefore examined whether modulators of phosphatidylinositol 3-kinase (PI3K)/AKT signaling affected JNK activation. PI3K inhibition led to increased JNK phosphorylation and islet cell death, which could be reversed by the specific JNK inhibitor SP600125. In addition, IGF-I suppressed cytokine-mediated JNK activation in a PI3K-dependent manner. We also demonstrate that inhibition of PI3K rendered islets more susceptible to cytokine-mediated cell death. SP600125 transiently protected islets from cytokine-mediated cell death, suggesting that JN...Continue Reading

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