Phorbol esters and dioctanoylglycerol block anti-IgM-stimulated phosphoinositide hydrolysis in the murine B cell lymphoma WEHI-231.
Cross-linking of membrane IgM (mIgM) on both normal resting B cells and on the murine B cell lymphoma WEHI-231 activates the phosphoinositide signal transduction pathway. The initial event in this pathway is the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdInsP2), which results in the generation of two second-messengers: inositol trisphosphate (InsP3), which can cause the release of Ca2+ from intracellular stores, and diacylglycerol (DG), which activates protein kinase C. In examining the effects of exogenous activation of protein kinase C on WEHI-231 cells, we found that phorbol esters blocked some of the biologic effects of anti-IgM on WEHI-231 cells. The mechanism of this effect was investigated. Phorbol ester treatment of WEHI-231 cells blocked the ability of anti-IgM to stimulate production of inositol phosphates and accumulation of phosphatidic acid, the phosphorylated product of DG. Phorbol esters also blocked the ability of anti-IgM to cause an increase in intracellular Ca2+. Thus, it is clear that phorbol esters block anti-IgM-stimulated PtdInsP2 hydrolysis in WEHI-231 cells. In addition, a synthetic DG, dioctanoylglycerol (diC8), also blocked anti-IgM-stimulated inositol phosphate production and the anti-IgM-stimulated rise in cytoplasmic Ca2+. The ability of phorbol esters and diC8 to block mIgM-mediated signaling may reflect a feedback inhibition mechanism by which activated protein kinase C limits the magnitude and duration of receptor signaling.
D001402:B-Lymphocytes / Q000378:metabolism; D002118:Calcium / Q000032:analysis; D002478:Cells, Cultured; D004075:Diglycerides / Q000494:pharmacology*; D004789:Enzyme Activation; D005989:Glycerides / Q000494:pharmacology*; D006868:Hydrolysis; D007075:Immunoglobulin M / Q000032:analysis / Q000276:immunology*; D008223:Lymphoma / Q000378:metabolism*; D010703:Phorbol Esters / Q000494:pharmacology*; D010712:Phosphatidic Acids / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism*; D011493:Protein Kinase C / Q000032:analysis; D011947:Receptors, Antigen, B-Cell / Q000032:analysis
D004075:Diglycerides; D005989:Glycerides; D007075:Immunoglobulin M; D010703:Phorbol Esters; D010712:Phosphatidic Acids; D010716:Phosphatidylinositols; D011947:Receptors, Antigen, B-Cell; C044295:1,2-dioctanoylglycerol; D011493:Protein Kinase C; D002118:Calcium