Exendin-4 protects beta-cells from interleukin-1 beta-induced apoptosis by interfering with the c-Jun NH2-terminal kinase pathway.

Details

Serval ID
serval:BIB_E0C5570050E9
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Exendin-4 protects beta-cells from interleukin-1 beta-induced apoptosis by interfering with the c-Jun NH2-terminal kinase pathway.
Journal
Diabetes
Author(s)
Ferdaoussi M., Abdelli S., Yang J.Y., Cornu M., Niederhauser G., Favre D., Widmann C., Regazzi R., Thorens B., Waeber G., Abderrahmani A.
ISSN
1939-327X[electronic], 0012-1797[linking]
Publication state
Published
Issued date
2008
Peer-reviewed
Oui
Volume
57
Number
5
Pages
1205-1215
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
OBJECTIVE: The pro-inflammatory cytokine interleukin-1 beta (IL-1 beta) generates pancreatic beta-cells apoptosis mainly through activation of the c-Jun NH(2)-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 cytokine-induced beta-cell apoptosis, could interfere with the JNK pathway. RESEARCH DESIGN AND METHODS: Isolated human, rat, and mouse islets and the rat insulin-secreting INS-1E cells were incubated with ex-4 in the presence or absence of IL-1 beta. 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-1 beta. This effect was mimicked with the use of cAMP-raising agents isobutylmethylxanthine and forskolin and required activation of the protein kinase A. Inhibition of the JNK pathway by ex-4 or IBMX and forskolin 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 IBMX and forskolin induced expression of IB1 at the promoter level through cAMP response element 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-1 beta. CONCLUSIONS: The data establish the requirement of IB1 in the protective action of ex-4 against apoptosis elicited by IL-1 beta and highlight the GLP-1 mimetics as new potent inhibitors of the JNK signaling induced by cytokines.
Keywords
Animals, Cell Line, Cells, Cultured, Enzyme Induction/drug effects, Hypoglycemic Agents/pharmacology, Insulin-Secreting Cells/cytology, Insulin-Secreting Cells/drug effects, Interleukin-1beta/pharmacology, Islets of Langerhans/cytology, JNK Mitogen-Activated Protein Kinases/biosynthesis, JNK Mitogen-Activated Protein Kinases/drug effects, Mice, Peptides/pharmacology, Rats, Venoms/pharmacology
Pubmed
Web of science
Open Access
Yes
Create date
20/02/2008 13:18
Last modification date
20/08/2019 16:04
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