Roles of mitogen-activated protein kinase pathways for mediator release from human cultured mast cells

Human cultured mast cells (HCMC) secrete histamine, sulfidoleukotrienes (LT s), and prostaglandin D-2 (PGD(2)), and produce a variety of cytokines afte r aggregation of high-affinity receptors for IgE (Fc epsilon RI). With resp ect to the mitogen-activated protein kinase (MAPK) family, extracellular si gnal-regulated kinases (ERKs), c-Jun NH2-terminal kinases (JNKs), and p38 m itogen-activated protein kinase (p38 MAPK) are known. To investigate the ro les of these kinase pathways for mediator release from human mast cells, we examined the participation of the activation of these kinases in mediator release, using 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene (U0126), an ERK pathway inhibitor, and 4-(4-fluorophenyl)-2-(4-methylsulfin ylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580), a p38 MAPK pathway inhibito r. U0126 inhibited ERK activation, LT and PGD(2) release, and granulocyte m acrophage-colony stimulating factor (GM-CSF) production after stimulation o f HCMC. SB203580, on the other hand, potentiated JNK activation and GM-CSF production. The findings of the present study demonstrated that: (i) the re lease of arachidonic acid metabolites is mediated by the ERK pathway; (ii) GM-CSF production may be driven by both the ERK and JNK pathways; and (iii) the p38 MAPK pathway negatively regulates the JNK pathway. This suggests t hat MAPK pathways play important roles in mediator release from human mast cells. BIOCHEM PHARMACOL 60;4:589-594, 2000. (C) 2000 Elsevier Science Inc.