Substance P can stimulate prostaglandin D2 and leukotriene C4 generation without granule exocytosis in murine mast cells.
Mast cells play a central role in immediate type hypersensitivity and inflammatory events. Activation of mast cells not only can result in the release of preformed granule-associated mediators generally followed by de novo synthesis of lipid-derived substances. In the present study, we show that mast cell can be activated to release lipid mediators in absence of granule exocytosis. Primary cultured murine mast cells were stimulated with substance P and produced leukotriene C4, and prostaglandin D2 without the release of the granule-associated enzyme beta-hexosaminidase. Indomethacin and nordihydroguaiaretic acid caused complete inhibition of arachidonic metabolite generation. Leukotriene C4 and prostaglandin D2 production was blocked by genistein, a specific inhibitor of tyrosine kinases, and bisindolylmaleimide, a protein kinase C inhibitor, indicating a role for both phosphorylation pathways in the substance P-stimulated lipid mediator production. We suggest that the cytokine microenvironment of the mast cell determines whether mast cell stimulation leads to only lipid mediator release or full activation. Analysis of granule-associated mediators only might underestimate the role of mast cell activation under (patho)physiological conditions.
Karimi
Khalil
K
Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Sorbonnelaan 16, P.O. Box 80.082, 3508 TB Utrecht, The Netherlands.
Kool
Mirjam
M
Nijkamp
Frans P
FP
Redegeld
Frank A
FA
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000648:ultrastructure; D003432:Cross-Linking Reagents / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003594:Cytoplasmic Granules / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005089:Exocytosis / Q000187:drug effects*; D019833:Genistein / Q000494:pharmacology; D007073:Immunoglobulin E / Q000096:biosynthesis; D007211:Indoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation / Q000473:pathology; D017997:Leukotriene C4 / Q000096:biosynthesis*; D008055:Lipids / Q000096:biosynthesis; D008301:Maleimides / Q000494:pharmacology; D009637:Masoprocol / Q000494:pharmacology; D008407:Mast Cells / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D015230:Prostaglandin D2 / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects; D013268:Stimulation, Chemical; D013373:Substance P / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D003432:Cross-Linking Reagents; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007211:Indoles; D008055:Lipids; D008301:Maleimides; D017997:Leukotriene C4; D013373:Substance P; D007073:Immunoglobulin E; D009637:Masoprocol; D019833:Genistein; C088060:bisindolylmaleimide; D015230:Prostaglandin D2; D007213:Indomethacin