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.

Implication of glycogen synthase kinase 3 in diabetes-associated islet inflammation

“…Chronic inflammation is known to exert toxic effects on β cell survival and function (Cnop et al 2005, Varin et al 2016. In order to evaluate the positive impact of the reduction of inflammation on the secretory function of islets, we measured the glucose-induced insulin secretion (GIIS) during static incubation experiments.…”

Exendin-4 improves neuron protection and functional recovery in experimental spinal cord injury in rats through regulating PCBP2 expression

“…Ex-4, as a glucagon-like peptide-1(GLP) receptor agonist, can effectively down-regulate blood glucose level, stimulate pancreatic β-cell regeneration, induce transcription of pro-insulin gene and promote maturation and secretion of insulin (31). Ex-4 can also stimulate the growth and proliferation of human β-cells, and suppress cytokine-induced apoptosis (32). Fanet al (33) demonstrated that Ex-4 could inhibit the apoptosis of retinal cell, balance the ratios of Bcl-2/Bax and Bcl-xL/Bax and decrease retinal reactive gliosis in diabetic Goto-Kakizaki rats.…”

Tumor progression locus 2 (TPL2) in tumor-promoting Inflammation, Tumorigenesis and Tumor Immunity

“…Several studies have implicated TPL2 in controlling inflammatory responses in non-hematopoietic cells that drive the pathogenesis of chronic inflammatory diseases, including neuroinflammation, lung inflammation, obesity-associated chronic inflammation, pancreatitis, hepatic inflammation and vascular inflammation 26 - 30 . Moreover, TPL2 is also implicated in the onset and progression of several inflammatory-related autoimmune diseases, including diabetes, multiple sclerosis (MS), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and thrombocytopenia (ITP) 31 - 35 . Collectively, these studies propose the importance of TPL2 kinase in propagating chronic inflammation that might drive malignant transformation through the production of inflammatory cytokines and the activation of various inflammatory and oncogenic signaling pathways.…”