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

• Published in: Biochemical pharmacology 2000-08, Vol.60 (4), p.589-594
• Main Authors: Kimata, Masahiro, Inagaki, Naoki, Kato, Toshinobu, Miura, Toru, Serizawa, Isao, Nagai, Hiroichi
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Butadienes - pharmacology; c-Jun NH 2-terminal kinases (JNKs); Cell physiology; Cells, Cultured; Enzyme Inhibitors - pharmacology; extracellular signal-regulated kinases (ERKs); Fundamental and applied biological sciences. Psychology; human cultured mast cells (HCMC); Humans; Imidazoles - pharmacology; Immunoglobulin E - immunology; JNK Mitogen-Activated Protein Kinases; MAP Kinase Signaling System - physiology; Mast Cells - drug effects; Mast Cells - enzymology; Mast Cells - metabolism; mediator release; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; Molecular and cellular biology; Nitriles - pharmacology; p38 mitogen-activated protein kinase (p38 MAPK); p38 Mitogen-Activated Protein Kinases; Pyridines - pharmacology; Signal transduction
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(00)00354-3

Human cultured mast cells (HCMC) secrete histamine, sulfidoleukotrienes (LTs), and prostaglandin D 2 (PGD 2), and produce a variety of cytokines after aggregation of high-affinity receptors for IgE (FcϵRI). With respect to the mitogen-activated protein kinase (MAPK) family, extracellular signal-regulated kinases (ERKs), c-Jun NH 2-terminal kinases (JNKs), and p38 mitogen-activated protein kinase (p38 MAPK) are known. To investigate the roles 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-methylsulfinylphenyl)-5-(4-pyridyl)1 H-imidazole (SB203580), a p38 MAPK pathway inhibitor. U0126 inhibited ERK activation, LT and PGD 2 release, and granulocyte macrophage-colony stimulating factor (GM-CSF) production after stimulation of HCMC. SB203580, on the other hand, potentiated JNK activation and GM-CSF production. The findings of the present study demonstrated that: (i) the release 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 that MAPK pathways play important roles in mediator release from human mast cells.