Group VIA PLA ₂ (iPLA ₂β) is activated upstream of p38 mitogen-activated protein kinase (MAPK) in pancreatic islet β-cell signaling

Group VIA phospholipase A ₂ (iPLA ₂β) 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 iPL _A2β activity and amplified by iPLA ₂β overexpression. While exploring signaling events that occur downstream of iPLA ₂β activation, we found that p38 MAPK is activated by phosphorylation in INS-1 insulinoma cells and mouse pancreatic islets, that this increases with iPLA ₂β expression level, and that it is stimulated by the iPLA ₂β reaction product arachidonic acid. The insulin secretagogue D-glucose also stimulates β-cell p38 MAPK phosphorylation, and this is prevented by the iPLA ₂β inhibitor bromoenol lactone. Insulin secretion induced by D-glucose and forskolin is amplified by overexpressing iPLA ₂β 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 β-cell MAPK kinase isoforms and p38 MAPK, and bromoenol lactone prevents both events. Others have reported that iPLA ₂β 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 β-cell p38 MAPK phosphorylation. Thapsigargin- induced β-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 ₂β in β-cells incubated with insulin secretagogues or thapsigargin, that this requires prior iPLA ₂β activation, and that p38 MAPK is involved in the β-cell functional responses of insulin secretion and apoptosis in which iPLA ₂β participates.