title: Inhibition of the MAP3 kinase Tpl2 protects rodent and human β-cells from apoptosis and dysfunction induced by cytokines and enhances anti-inflammatory actions of exendin-4.
abstract: Proinflammatory cytokines exert cytotoxic effects on β-cells, and are involved in the pathogenesis of type I and type II diabetes and in the drastic loss of β-cells following islet transplantation. Cytokines induce apoptosis and alter the function of differentiated β-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 β-cells is unknown. We demonstrate that Tpl2 is expressed in INS-1E β-cells, mouse and human islets, is activated and upregulated by cytokines and mediates ERK1/2, JNK and p38 activation. Tpl2 inhibition protects β-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 β-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 β-cells.
authors.affiliation: INSERM U1191, Institute of Functional Genomic (IGF), CNRS UMR5203, Montpellier University, Montpellier, France.|Laboratory of Cellular Therapy of Diabetes (LTCD), Institute of Regenerative Medicine and Biotherapy (IMRB), University Hospital of Montpellier, Montpellier, France.
authors.forename: E M
authors.initials: EM
authors.lastname: Varin
authors.affiliation: INSERM U1191, Institute of Functional Genomic (IGF), CNRS UMR5203, Montpellier University, Montpellier, France.|Laboratory of Cellular Therapy of Diabetes (LTCD), Institute of Regenerative Medicine and Biotherapy (IMRB), University Hospital of Montpellier, Montpellier, France.|Department of Endocrinology, Diabetes, and Nutrition, University Hospital of Montpellier, Montpellier, France.
authors.forename: A
authors.initials: A
authors.lastname: Wojtusciszyn
authors.affiliation: Laboratory of Cellular Therapy of Diabetes (LTCD), Institute of Regenerative Medicine and Biotherapy (IMRB), University Hospital of Montpellier, Montpellier, France.
authors.forename: C
authors.initials: C
authors.lastname: Broca
authors.affiliation: INSERM U1191, Institute of Functional Genomic (IGF), CNRS UMR5203, Montpellier University, Montpellier, France.
authors.forename: D
authors.initials: D
authors.lastname: Muller
authors.affiliation: INSERM U1191, Institute of Functional Genomic (IGF), CNRS UMR5203, Montpellier University, Montpellier, France.
authors.forename: M A
authors.initials: MA
authors.lastname: Ravier
authors.affiliation: INSERM U1065, Mediterranean Center of Molecular Medicine, University of Nice Sophia-Antipolis, Faculty of Medicine, Nice, France.
authors.forename: F
authors.initials: F
authors.lastname: Ceppo
authors.affiliation: INSERM U1191, Institute of Functional Genomic (IGF), CNRS UMR5203, Montpellier University, Montpellier, France.|Laboratory of Cellular Therapy of Diabetes (LTCD), Institute of Regenerative Medicine and Biotherapy (IMRB), University Hospital of Montpellier, Montpellier, France.|Department of Endocrinology, Diabetes, and Nutrition, University Hospital of Montpellier, Montpellier, France.
authors.forename: E
authors.initials: E
authors.lastname: Renard
authors.affiliation: INSERM U1065, Mediterranean Center of Molecular Medicine, University of Nice Sophia-Antipolis, Faculty of Medicine, Nice, France.
authors.forename: J-F
authors.initials: JF
authors.lastname: Tanti
authors.affiliation: INSERM U1191, Institute of Functional Genomic (IGF), CNRS UMR5203, Montpellier University, Montpellier, France.|Laboratory of Cellular Therapy of Diabetes (LTCD), Institute of Regenerative Medicine and Biotherapy (IMRB), University Hospital of Montpellier, Montpellier, France.|Department of Endocrinology, Diabetes, and Nutrition, University Hospital of Montpellier, Montpellier, France.
authors.forename: S
authors.initials: S
authors.lastname: Dalle
mesh_terms: D017209:Apoptosis; D002908:Chronic Disease; D016207:Cytokines; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology* / Q000473:pathology; D000077270:Exenatide; D006801:Humans; D007249:Inflammation; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D014688:Venoms / Q000378:metabolism*
chemical_list: D016207:Cytokines; D010455:Peptides; D014688:Venoms; D000077270:Exenatide; D020930:MAP Kinase Kinase Kinases