High glucose induces suppression of insulin signalling and apoptosis via upregulation of endogenous IL-1β and suppressor of cytokine signalling-1 in mouse pancreatic beta cells

Venieratos, Panagiotis D.; Drossopoulou, Garyfalia I.; Kapodistria, Katerina; Tsilibary, Effie C.; Kitsiou, Paraskevi V.

doi:10.1016/j.cellsig.2010.01.003

Cited by 39 publications

(30 citation statements)

References 53 publications

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“…Modulation of SOCS expression by glucose has been previously shown with higher expression levels in a variety of human cells (38,39,41). To our knowledge, our data presented here within are the first to demonstrate increased SOCS-1 and -3 expression by glucose in TC-EC.…”

Section: Discussionsupporting

confidence: 58%

Cell matrix contact modifies endothelial major histocompatibility complex class II expression in high-glucose environment

Nickmann

Saemisch

Wilbert-Lampen

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Atherosclerosis is a chronic inflammatory disease. Cardiovascular risk factors such as hyperglycemia, hyperlipidemia, and arterial hypertension induce endothelial dysfunction with alterations in endothelial biosecretion and immune behavior. The aim of this study is to elucidate whether glucose-induced modifications of endothelial biosecretory and immune functions are regulated by interactions of endothelial cells (ECs) with their extracellular matrix [ECs plated on polystyrene-coated tissue culture plates (TC-EC) vs. ECs embedded within three-dimensional (3-D) collagen-based matrixes (3D-EC)]. In the absence of glucose, IFN-γ-induced phosphorylation of JAK and STAT proteins and human leukocyte antigen (HLA)-DR expression were lower in 3D-EC compared with TC-EC. Inversely, the expression of suppressor of cytokine signaling proteins (SOCS)-1 and -3 were significantly higher in naïve 3D-EC compared with naïve TC-EC. IFN-γ-induced upregulation of SOCS proteins was further amplified by the 3-D environment. Glucose significantly augmented IFN-γ-dependent signaling pathways in TC-EC. IFN-γ-induced phosphorylation of JAK and STAT proteins as well as HLA-DR expression by ECs in low- and high-glucose medium was significantly lower in 3-D than in two-dimensional environment. Glucose increased SOCS expression in TC-EC and 3D-EC to the same extent, such that expression levels in 3D-EC exceeded SOCS-1 and -3 expression in TC-EC by 1.6–2.5-fold. In conclusion, low- and high-glucose concentrations amplify IFN-γ-induced signaling pathways in TC-EC. Increased SOCS expression raises the threshold for IFN-γ to induce HLA-DR expression in a 3-D environment. This immunoprotective effect is maintained even in states of experimental hyperglycemia.

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Section: Discussionsupporting

confidence: 58%

Cell matrix contact modifies endothelial major histocompatibility complex class II expression in high-glucose environment

Nickmann

Saemisch

Wilbert-Lampen

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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“…Other studies have shown that Akt activity can be inhibited by proinflammatory cytokines (42,43). We therefore examined whether TRB3 knockdown attenuated the ability of cytokines to inhibit Akt Ser 473 phosphorylation (Fig.…”

Section: Figure 2 Mlk-dependent Induction Of Proapoptotic Markers Inmentioning

confidence: 99%

Mixed Lineage Kinase-3 Stabilizes and Functionally Cooperates with TRIBBLES-3 to Compromise Mitochondrial Integrity in Cytokine-induced Death of Pancreatic Beta Cells

Humphrey

Newcomb

et al. 2010

Journal of Biological Chemistry

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Mixed lineage kinases (MLKs) have been implicated in cytokine signaling as well as in cell death pathways. Our studies show that MLK3 is activated in leukocyte-infiltrated islets of nonobese diabetic mice and that MLK3 activation compromises mitochondrial integrity and induces apoptosis of beta cells. Using an ex vivo model of islet-splenocyte co-culture, we show that MLK3 mediates its effects via the pseudokinase TRB3, a mammalian homolog of Drosophila Tribbles. TRB3 expression strongly coincided with conformational change and mitochondrial translocation of BAX. Mechanistically, MLK3 directly interacted with and stabilized TRB3, resulting in inhibition of Akt, a strong suppressor of BAX translocation and mitochondrial membrane permeabilization. Accordingly, attenuation of MLK3 or TRB3 expression each prevented cytokine-induced BAX conformational change and attenuated the progression to apoptosis. We conclude that MLKs compromise mitochondrial integrity and suppress cellular survival mechanisms via TRB3-dependent inhibition of Akt.In type 1 diabetes, the autoimmune destruction of pancreatic beta cells is driven by leukocyte infiltration and the damaging effects of locally secreted cytokines. Cytokines activate MAPKs 3 JNK and p38, via signaling modules that involve the sequential activation of a MAP3K, MAP2K, and MAPK, all scaffolded by a single protein (1). The existence of several families of MAP3Ks raises the possibility that each MAP3K may be activated by specific classes of stimuli. The serine-threonine MAP3K mixed lineage kinase-3 (MLK3) is activated by cytokines (2, 3) and assembles a signaling module consisting of MKK7, JNK, and the scaffold protein JIP1 (4, 5). Fibroblasts with a targeted deletion of either MKK7 or MLK3 are attenuated in their response to cytokines (6, 7). Elevation of MLK3 has been linked to induction of apoptosis in neurons (8 -10), and inhibition of MLKs can delay progression of neurodegenerative diseases (reviewed in Ref. 11 and studies quoted therein). The striking parallels between the beta cell and neuronal phenotypes, coupled with the ability of cytokines to activate MLK3, prompted us to examine whether MLKs participate in cytokine-induced beta cell death.Here we show that MLK3 is markedly elevated in leukocyteinfiltrated islets of the non-obese type 1 diabetic (NOD) mouse. To investigate the potential role of MLK3 in beta cell death, we devised an ex vivo system for co-culture of primary islets with immune-activated splenocytes. Compared with static culture with purified cytokines, this system is likely to be more representative of the milieu encountered by islets in autoimmune diabetes. We observed rapid activation of MLK3, and MLK3 was required for cytokine-mediated apoptosis via BAX, a proapoptotic member of the BCL-2 protein family. MLK3 mediated its effects via the pseudokinase TRB3 (TRIBBLES homolog 3), originally identified as an inducible factor in neuronal cell death (12) and subsequently shown to be a potent negative regulator of the prosurvival kinase Akt (13). We fo...

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“…We have reported that endothelial insulin receptor apoE knockout mice (EIRAKO) with double knockout of apolipoprotein E (apoE Ϫ/Ϫ ) and insulin receptor (IR Ϫ/Ϫ ) developed significantly more atherosclerosis than apoE Ϫ/Ϫ mice, suggesting the physiological importance of insulin for endothelial cells (4). Recent studies have shown clearly that multiple factors can selectively inhibit insulin action via the activation of IRS/PI3 kinase and Akt pathways, such as hyperglycemia, free fatty acids, protein kinase C (PKC) activation, angiotensin, and diabetes (5)(6)(7)(8). Although both IRS1 and IRS2 are expressed on the endothelium, it remains unclear whether they can induce similar profiles of action, since both can activate PI3 kinase and p-Akt.…”

mentioning

confidence: 99%

Serine Phosphorylation Sites on IRS2 Activated by Angiotensin II and Protein Kinase C To Induce Selective Insulin Resistance in Endothelial Cells

Park

Rask‐Madsen

et al. 2013

Molecular and Cellular Biology

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Protein kinase C (PKC) activation, induced by hyperglycemia and angiotensin II (AngII), inhibited insulin-induced phosphorylation of Akt/endothelial nitric oxide (eNOS) by decreasing tyrosine phosphorylation of IRS2 (p-Tyr-IRS2) in endothelial cells. PKC activation by phorbol ester (phorbol myristate acetate [PMA]) reduced insulin-induced p-Tyr-IRS2 by 46% ± 13% and, similarly, phosphorylation of Akt/eNOS. Site-specific mutational analysis showed that PMA increased serine phosphorylation at three sites on IRS2 (positions 303, 343, and 675), which affected insulin-induced tyrosine phosphorylation of IRS2 at positions 653, 671, and 911 (p-Tyr-IRS2) and p-Akt/eNOS. Specific PKCβ2 activation decreased p-Tyr-IRS2 and increased the phosphorylation of two serines (Ser303 and Ser675) on IRS2 that were confirmed in cells overexpressing single point mutants of IRS2 (S303A or S675A) containing a PKCβ2-dominant negative or selective PKCβ inhibitor. AngII induced phosphorylation only on Ser303 of IRS2 and inhibited insulin-induced p-Tyr911 of IRS2 and p-Akt/eNOS, which were blocked by an antagonist of AngII receptor I, losartan, or overexpression of single mutant S303A of IRS2. Increases in p-Ser303 and p-Ser675 and decreases in p-Tyr911 of IRS2 were observed in vessels of insulin-resistant Zucker fatty rats versus lean rats. Thus, AngII or PKCβ activation can phosphorylate Ser303 and Ser675 in IRS2 to inhibit insulin-induced p-Tyr911 and its anti-atherogenic actions (p-Akt/eNOS) in endothelial cells.

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High glucose induces suppression of insulin signalling and apoptosis via upregulation of endogenous IL-1β and suppressor of cytokine signalling-1 in mouse pancreatic beta cells

Cited by 39 publications

References 53 publications

Cell matrix contact modifies endothelial major histocompatibility complex class II expression in high-glucose environment

Cell matrix contact modifies endothelial major histocompatibility complex class II expression in high-glucose environment

Mixed Lineage Kinase-3 Stabilizes and Functionally Cooperates with TRIBBLES-3 to Compromise Mitochondrial Integrity in Cytokine-induced Death of Pancreatic Beta Cells

Serine Phosphorylation Sites on IRS2 Activated by Angiotensin II and Protein Kinase C To Induce Selective Insulin Resistance in Endothelial Cells

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