Inhibition of the MAP3 kinase Tpl2 protects rodent and human beta-cells from apoptosis and dysfunction induced by cytokines and enhances anti-inflammatory actions of exendin-4

Details

Serval ID
serval:BIB_FD59B76D2DA5
Type
Article: article from journal or magazin.
Collection
Publications
Title
Inhibition of the MAP3 kinase Tpl2 protects rodent and human beta-cells from apoptosis and dysfunction induced by cytokines and enhances anti-inflammatory actions of exendin-4
Journal
Cell Death Dis
Author(s)
Varin E. M., Wojtusciszyn A., Broca C., Muller D., Ravier M. A., Ceppo F., Renard E., Tanti J. F., Dalle S.
ISSN
2041-4889 (Electronic)
Publication state
Published
Issued date
2016
Volume
7
Pages
e2065
Language
english
Notes
Varin, E M
Wojtusciszyn, A
Broca, C
Muller, D
Ravier, M A
Ceppo, F
Renard, E
Tanti, J-F
Dalle, S
eng
Research Support, Non-U.S. Gov't
England
Cell Death Dis. 2016 Jan 21;7:e2065. doi: 10.1038/cddis.2015.399.
Abstract
Proinflammatory cytokines exert cytotoxic effects on beta-cells, and are involved in the pathogenesis of type I and type II diabetes and in the drastic loss of beta-cells following islet transplantation. Cytokines induce apoptosis and alter the function of differentiated beta-cells. Although the MAP3 kinase tumor progression locus 2 (Tpl2) is known to integrate signals from inflammatory stimuli in macrophages, fibroblasts and adipocytes, its role in beta-cells is unknown. We demonstrate that Tpl2 is expressed in INS-1E beta-cells, mouse and human islets, is activated and upregulated by cytokines and mediates ERK1/2, JNK and p38 activation. Tpl2 inhibition protects beta-cells, mouse and human islets from cytokine-induced apoptosis and preserves glucose-induced insulin secretion in mouse and human islets exposed to cytokines. Moreover, Tpl2 inhibition does not affect survival or positive effects of glucose (i.e., ERK1/2 phosphorylation and basal insulin secretion). The protection against cytokine-induced beta-cell apoptosis is strengthened when Tpl2 inhibition is combined with the glucagon-like peptide-1 (GLP-1) analog exendin-4 in INS-1E cells. Furthermore, when combined with exendin-4, Tpl2 inhibition prevents cytokine-induced death and dysfunction of human islets. This study proposes that Tpl2 inhibitors, used either alone or combined with a GLP-1 analog, represent potential novel and effective therapeutic strategies to protect diabetic beta-cells.
Keywords
Apoptosis, Chronic Disease, Cytokines, Diabetes Mellitus, Type 2/*etiology/pathology, Exenatide, Humans, Inflammation, MAP Kinase Kinase Kinases/*metabolism, Peptides/*metabolism, Venoms/*metabolism
Pubmed
Create date
14/06/2021 8:59
Last modification date
18/09/2021 5:38
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