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Exendin-4 protects beta-cells from interleukin-1 beta-induced apoptosis by interfering with the c-Jun NH2-terminal kinase pathway.
Diabetes 2008; 57(5):1205-15D

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.

Authors+Show Affiliations

Service of Internal Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18252896

Citation

Ferdaoussi, Mourad, et al. "Exendin-4 Protects Beta-cells From Interleukin-1 Beta-induced Apoptosis By Interfering With the c-Jun NH2-terminal Kinase Pathway." Diabetes, vol. 57, no. 5, 2008, pp. 1205-15.
Ferdaoussi M, Abdelli S, Yang JY, et al. Exendin-4 protects beta-cells from interleukin-1 beta-induced apoptosis by interfering with the c-Jun NH2-terminal kinase pathway. Diabetes. 2008;57(5):1205-15.
Ferdaoussi, M., Abdelli, S., Yang, J. Y., Cornu, M., Niederhauser, G., Favre, D., ... Abderrahmani, A. (2008). Exendin-4 protects beta-cells from interleukin-1 beta-induced apoptosis by interfering with the c-Jun NH2-terminal kinase pathway. Diabetes, 57(5), pp. 1205-15. doi:10.2337/db07-1214.
Ferdaoussi M, et al. Exendin-4 Protects Beta-cells From Interleukin-1 Beta-induced Apoptosis By Interfering With the c-Jun NH2-terminal Kinase Pathway. Diabetes. 2008;57(5):1205-15. PubMed PMID: 18252896.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Exendin-4 protects beta-cells from interleukin-1 beta-induced apoptosis by interfering with the c-Jun NH2-terminal kinase pathway. AU - Ferdaoussi,Mourad, AU - Abdelli,Saida, AU - Yang,Jiang-Yan, AU - Cornu,Marion, AU - Niederhauser,Guy, AU - Favre,Dimitri, AU - Widmann,Christian, AU - Regazzi,Romano, AU - Thorens,Bernard, AU - Waeber,Gérard, AU - Abderrahmani,Amar, Y1 - 2008/02/05/ PY - 2008/2/7/pubmed PY - 2008/8/5/medline PY - 2008/2/7/entrez SP - 1205 EP - 15 JF - Diabetes JO - Diabetes VL - 57 IS - 5 N2 - 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. SN - 1939-327X UR - https://www.unboundmedicine.com/medline/citation/18252896/Exendin_4_protects_beta_cells_from_interleukin_1_beta_induced_apoptosis_by_interfering_with_the_c_Jun_NH2_terminal_kinase_pathway_ L2 - http://diabetes.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=18252896 DB - PRIME DP - Unbound Medicine ER -