Titre
Exendin-4 protects beta-cells from interleukin-1 beta-induced apoptosis by interfering with the c-Jun NH2-terminal kinase pathway.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Ferdaoussi, M.
Auteure/Auteur
Abdelli, S.
Auteure/Auteur
Yang, J.Y.
Auteure/Auteur
Cornu, M.
Auteure/Auteur
Niederhauser, G.
Auteure/Auteur
Favre, D.
Auteure/Auteur
Widmann, C.
Auteure/Auteur
Regazzi, R.
Auteure/Auteur
Thorens, B.
Auteure/Auteur
Waeber, G.
Auteure/Auteur
Abderrahmani, A.
Auteure/Auteur
Liens vers les unités
ISSN
1939-327X[electronic], 0012-1797[linking]
Statut éditorial
Publié
Date de publication
2008
Volume
57
Numéro
5
Première page
1205
Dernière page/numéro d’article
1215
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Résumé
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.
PID Serval
serval:BIB_E0C5570050E9
PMID
Open Access
Oui
Date de création
2008-02-20T12:18:51.714Z
Date de création dans IRIS
2025-05-20T22:51:55Z