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Group VIA PLA2 (iPLA2?) is activated upstream of p38 mitogen-activated protein kinase (MAPK) in pancreatic islet ?-cell signaling.

ABSTRACT: Group VIA phospholipase A(2) (iPLA(2)?) in pancreatic islet ?-cells participates in glucose-stimulated insulin secretion and sarco(endo)plasmic reticulum ATPase (SERCA) inhibitor-induced apoptosis, and both are attenuated by pharmacologic or genetic reductions in iPLA(2)? activity and amplified by iPLA(2)? overexpression. While exploring signaling events that occur downstream of iPLA(2)? activation, we found that p38 MAPK is activated by phosphorylation in INS-1 insulinoma cells and mouse pancreatic islets, that this increases with iPLA(2)? expression level, and that it is stimulated by the iPLA(2)? reaction product arachidonic acid. The insulin secretagogue D-glucose also stimulates ?-cell p38 MAPK phosphorylation, and this is prevented by the iPLA(2)? inhibitor bromoenol lactone. Insulin secretion induced by d-glucose and forskolin is amplified by overexpressing iPLA(2)? in INS-1 cells and in mouse islets, and the p38 MAPK inhibitor PD169316 prevents both responses. The SERCA inhibitor thapsigargin also stimulates phosphorylation of both ?-cell MAPK kinase isoforms and p38 MAPK, and bromoenol lactone prevents both events. Others have reported that iPLA(2)? products activate Rho family G-proteins that promote MAPK kinase activation via a mechanism inhibited by Clostridium difficile toxin B, which we find to inhibit thapsigargin-induced ?-cell p38 MAPK phosphorylation. Thapsigargin-induced ?-cell apoptosis and ceramide generation are also prevented by the p38 MAPK inhibitor PD169316. These observations indicate that p38 MAPK is activated downstream of iPLA(2)? in ?-cells incubated with insulin secretagogues or thapsigargin, that this requires prior iPLA(2)? activation, and that p38 MAPK is involved in the ?-cell functional responses of insulin secretion and apoptosis in which iPLA(2)? participates.

SUBMITTER: Song H

PROVIDER: S-EPMC3285329 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Group VIA PLA2 (iPLA2β) is activated upstream of p38 mitogen-activated protein kinase (MAPK) in pancreatic islet β-cell signaling.

Song Haowei H Wohltmann Mary M Tan Min M Bao Shunzhong S Ladenson Jack H JH Turk John J

The Journal of biological chemistry 20111222 8

Group VIA phospholipase A(2) (iPLA(2)β) in pancreatic islet β-cells participates in glucose-stimulated insulin secretion and sarco(endo)plasmic reticulum ATPase (SERCA) inhibitor-induced apoptosis, and both are attenuated by pharmacologic or genetic reductions in iPLA(2)β activity and amplified by iPLA(2)β overexpression. While exploring signaling events that occur downstream of iPLA(2)β activation, we found that p38 MAPK is activated by phosphorylation in INS-1 insulinoma cells and mouse pancre ...[more]

PMID: 22194610

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Project description:AimsSome asthma patients remain symptomatic despite using high doses of inhaled corticosteroids (ICS). We used alveolar macrophages to identify individual patients with insensitivity to corticosteroids and to evaluate the anti-inflammatory effects of a p38 mitogen-activated protein kinase (MAPK) inhibitor combined with a corticosteroid on these cells.MethodsAlveolar macrophages from 27 asthma patients (classified according to the Global Initiative for Asthma (GINA) treatment stage. Six GINA1, 10 GINA2 and 11 GINA3/4) were stimulated with lipoploysaccharide (LPS) (1 ?g ml(-1)). The effects of dexamethasone (dex 1-1000 nm), the p38 MAPK inhibitor 1-(5-tert-butyl-2-p-tolyl-2Hpyrazol-3-yl)-3(4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl)urea (BIRB-796 1-1000 nm) and both drugs combined at all concentrations on supernatant TNF?, IL-6 and CXCL-8 concentrations were analyzed by ELISA. Dose-sparing and efficacy enhancing effects of combination treatment were determined.ResultsDexamethasone reduced LPS-induced TNF?, IL-6 and CXCL-8 in all groups, but maximum inhibition was significantly reduced for GINA3/4 compared with GINA2 and GINA1 (P < 0.01). A subgroup of corticosteroid insensitive patients with a reduced effect of dexamethasone on cytokine secretion were identified. BIRB-796 in combination with dexamethasone significantly increased cytokine inhibition compared with either drug alone (P < 0.001) in all groups. This effect was greater in corticosteroid insensitive compared with sensitive patients. There were significant synergistic dose-sparing effects (P < 0.05) for the combination treatment on inhibition of TNF?, IL-6 and CXCL-8 in all groups. There was also significant efficacy enhancing benefits (P < 0.05) on TNF? and IL-6.Conclusionsp38 MAPK inhibitors synergistically enhance efficacy of corticosteroids in macrophages from asthma patients. This effect is greater in corticosteroid insensitive asthma patients, suggesting that this class of drug should be targeted to this patient phenotype.

Dataset Information

Group VIA PLA2 (iPLA2?) is activated upstream of p38 mitogen-activated protein kinase (MAPK) in pancreatic islet ?-cell signaling.

Publications

Group VIA PLA2 (iPLA2β) is activated upstream of p38 mitogen-activated protein kinase (MAPK) in pancreatic islet β-cell signaling.

Similar Datasets

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