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Exendin-4 protects β-cells from interleukin 1β-induced apoptosis by interfering with the c-Jun N-terminal kinases pathway

¹Service of Internal Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, CH-1011 Lausanne, Switzerland
²Department of Cellular Biology and Morphology, University of Lausanne, CH-1005 Lausanne, Switzerland
³Department of Physiology, University of Lausanne, CH-1005 Lausanne, Switzerland
⁴Center for integrative Genomics, University of Lausanne, CH-1005 Lausanne, Switzerland

Objective: The pro-inflammatory cytokine interleukin-1β (IL-1β) generates pancreatic β-cells apoptosis mainly through activation of the c-Jun Amino terminal Kinase (JNK) pathway. This study was designed to investigate whether the long-acting agonist of the hormone Glucagon-like peptide-1 (GLP-1) receptor exendin-4 (ex-4), which mediates protective effects against-cytokines-induced β-cell apoptosis, could interfere with the JNK pathway.

Research Design and Methods: Isolated human, rat and mouse islets as well as the rat insulin-secreting INS-1E cells were incubated with ex-4 in the presence or absence of IL-1β. JNK activity was assessed by solid-phase JNK kinase assay and quantification of c-Jun expression. Cell apoptosis was determined by scoring cells displaying pycnotic nuclei

Results: Ex-4 inhibited induction of the JNK pathway elicited by IL-1β. This effect was mimicked with the use of cAMP-raising agents IBMX and Foskolin (I/F) and required activation of the protein kinase A (PKA). Inhibition of the JNK pathway by ex-4 and I/F was concomitant with a rise in the levels of Islet-Brain 1 (IB1), a potent blocker of the stress-induced JNK pathway. In fact, ex-4 as well as I/F induced expression of IB1 at the promoter level through the CRE binding transcription factor 1. Suppression of IB1 levels with the use of RNA interference strategy impaired the protective effects of ex-4 against apoptosis induced by IL-1β

Conclusion: The data establish the requirement of IB1 in the protective action of ex-4 against apoptosis elicited by IL-1β and highlight the GLP-1 mimetics as new potent inhibitors of the JNK signalling induced by cytokines.

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