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

• Published in: Cell death & disease 2016-01, Vol.7 (1), p.e2065-e2065
• Main Authors: Varin, E M, Wojtusciszyn, A, Broca, C, Muller, D, Ravier, M A, Ceppo, F, Renard, E, Tanti, J-F, Dalle, S
• Format: Article
• Language: English
• Subjects: 13/106; 13/2; 13/21; 13/95; 631/250/256; 631/45/127; 631/80/82/23; 692/699/2743/137; 96/109; Antibodies; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cellular Biology; Chronic Disease; Cytokines; Diabetes Mellitus, Type 2 - etiology; Diabetes Mellitus, Type 2 - pathology; Endocrinology and metabolism; Human health and pathology; Humans; Immunology; Inflammation; Life Sciences; MAP Kinase Kinase Kinases - metabolism; Original; original-article; Peptides - metabolism; Venoms - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2015.399

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.