Exendin-4 Protects β-Cells From Interleukin-1β–Induced Apoptosis by Interfering With the c-Jun NH2-Terminal Kinase Pathway
- Mourad Ferdaoussi12,
- Saida Abdelli12,
- Jiang-Yan Yang23,
- Marion Cornu34,
- Guy Niederhauser12,
- Dimitri Favre12,
- Christian Widmann23,
- Romano Regazzi2,
- Bernard Thorens34,
- Gérard Waeber1 and
- Amar Abderrahmani12
- 1Service of Internal Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
- 2Department of Cellular Biology and Morphology, University of Lausanne, Lausanne, Switzerland
- 3Department of Physiology, University of Lausanne, Lausanne, Switzerland
- 4Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
- Corresponding author: Dr. Amar Abderrahmani, Privat-Docent, Department of Cellular Biology and Morphology, Rue du Bugnon 9, 1005 Lausanne, Switzerland. E-mail: amar.abderrahmani{at}unil.ch
Abstract
OBJECTIVE— The pro-inflammatory cytokine interleukin-1β (IL-1β) generates pancreatic β-cells apoptosis mainly through activation of the c-Jun NH2-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 β-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-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 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-1β.
CONCLUSIONS— 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 signaling induced by cytokines.
Footnotes
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Published ahead of print at http://diabetes.diabetesjournals.org on 5 February 2008. DOI: 10.2337/db07-1214.
ChIP, chromatin immunoprecipitation; CRE, cAMP response element; CREB, CRE–binding protein; EMSA, electromobility shift assay; ex-4, exendin-4; GFP, green fluorescent protein; GLP-1, glucagon-like peptide 1; GLP-1R, GLP-1 receptor; GST, glutathione S-transferase; HES-1, hairy and enhancer of split-1; IB1, islet-brain 1; IBMX, isobutylmethylxanthine; ICER, inducible cAMP early repressor; IL, interleukin; JBD, c-Jun NH2-terminal kinase binding domain; JNK, c-Jun NH2-terminal kinase; JNKi, JBD of IB1; MAPK, mitogen-activated protein kinase; PI 3-kinase, phosphatidylinositol 3-kinase; PKA, protein kinase A; PKB, protein kinase B; RNAi, RNA interference; shIB1, target-specific shRNA directed against IB1; shRNA, short hairpin RNA; siRNA, small interfering RNA.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Accepted January 30, 2008.
- Received August 29, 2007.
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