Karimi Khalil, Kool Mirjam, Nijkamp Frans P, Redegeld Frank A
Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Sorbonnelaan 16, P.O. Box 80.082, 3508 TB Utrecht, The Netherlands.
Eur J Pharmacol. 2004 Apr 5;489(1-2):49-54. doi: 10.1016/j.ejphar.2004.03.003.
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.
肥大细胞在速发型超敏反应和炎症事件中起核心作用。肥大细胞的激活不仅可导致预先形成的颗粒相关介质的释放，随后通常还会从头合成脂质衍生物质。在本研究中，我们表明肥大细胞可在无颗粒胞吐作用的情况下被激活以释放脂质介质。用P物质刺激原代培养的小鼠肥大细胞，可产生白三烯C4和前列腺素D2，而不释放颗粒相关酶β-己糖胺酶。吲哚美辛和去甲二氢愈创木酸可完全抑制花生四烯酸代谢产物的生成。白三烯C4和前列腺素D2的产生被酪氨酸激酶的特异性抑制剂染料木黄酮和蛋白激酶C抑制剂双吲哚马来酰亚胺阻断，这表明两种磷酸化途径在P物质刺激的脂质介质产生中均起作用。我们认为肥大细胞的细胞因子微环境决定了肥大细胞刺激是否仅导致脂质介质释放或完全激活。仅分析颗粒相关介质可能会低估肥大细胞激活在（病理）生理条件下的作用。
