Gibbs B F, Grabbe J
Department of Dermatology, Medical University of Lübeck, Germany.
J Leukoc Biol. 1999 Jun;65(6):883-90. doi: 10.1002/jlb.65.6.883.
Effects of inhibitors of PI 3-kinase and MEK kinases were investigated on histamine, leukotriene C4(LTC4), and cytokine release from human basophils stimulated with anti-IgE. The PI 3-kinase antagonists wortmannin (> 10 nM) and LY 294002 (>1 microM) strongly inhibited anti-IgE-induced release of all mediators by 40-100%. This was contrasted by the effects of the MEK kinase inhibitor PD 098059, which weakly inhibited histamine, interleukin (IL)-4, and IL-13 release but was substantially more efficacious at blocking LTC4 production (>70% at 10 microM). Previous studies have shown that arachidonic acid synthesis is controlled by MEK kinases. We observed that wortmannin, LY 294002, and PD 098059 reduce basophil ERK-1,2 activation, thus implying that, with regard to arachidonic acid metabolism, MEK kinases are a downstream target for PI-3-kinase. Our results demonstrate a universal regulatory role played by PI 3-kinases in basophil mediator production and release, whereas MEK kinase signaling is largely limited to controlling arachidonic acid metabolism.
研究了PI 3激酶和MEK激酶抑制剂对用抗IgE刺激的人嗜碱性粒细胞释放组胺、白三烯C4（LTC4）和细胞因子的影响。PI 3激酶拮抗剂渥曼青霉素（>10 nM）和LY 294002（>1 microM）强烈抑制抗IgE诱导的所有介质释放，抑制率为40%-100%。与之形成对比的是，MEK激酶抑制剂PD 098059对组胺、白细胞介素（IL）-4和IL-13释放的抑制作用较弱，但在阻断LTC4产生方面更有效（10 microM时>70%）。先前的研究表明，花生四烯酸合成受MEK激酶控制。我们观察到渥曼青霉素、LY 294002和PD 098059可降低嗜碱性粒细胞ERK-1,2的活化，因此这意味着，就花生四烯酸代谢而言，MEK激酶是PI-3激酶的下游靶点。我们的结果表明，PI 3激酶在嗜碱性粒细胞介质产生和释放中发挥普遍的调节作用，而MEK激酶信号传导在很大程度上仅限于控制花生四烯酸代谢。
