Analysis of signal transduction pathways in human eosinophils activated by chemoattractants and the T-helper 2-derived cytokines interleukin-4 and interleukin-5
Analysis of signal transduction pathways in human eosinophils activated by chemoattractants and the T-helper 2-derived cytokines interleukin-4 and interleukin-5
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DOI：
10.1182/blood.v91.7.2547.2547_2547_2557
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发表时间：
1998-04-01
期刊：
影响因子：
20.3
通讯作者：
Koenderman, L
中科院分区：
文献类型：
--
作者：
Coffer, PJ;Schweizer, RC;Koenderman, L
过敏性炎症中嗜酸性粒细胞的激活和募集部分由趋化因子和辅助性T细胞2（Th 2）衍生的细胞因子介导。然而，很少有人知道有关的信号转导机制，这种激活发生。我们研究了酪氨酸激酶介导的磷脂酰肌醇3-激酶（PI 3 K）的激活，并将其与人嗜酸性粒细胞中p21 ras-ERK信号通路的激活进行了比较。相关细胞因子白细胞介素-3（IL-3）、IL-5和粒细胞-巨噬细胞集落刺激因子（GM-CSF）均诱导PI 3 K活性，在抗磷酸酪氨酸免疫沉淀物中检测到。此外，趋化因子血小板活化因子（PAF），RANTES和C5 a也能够诱导磷酸酪氨酸相关的PI 3 K活性。蛋白激酶B（PKB）是生长因子激活PI 3 K的下游靶点。人嗜酸性粒细胞中PKB磷酸化的诱导在用细胞因子IL-0和IL-5以及化学引诱物PAF、C5 a和RANTES活化时瞬时诱导，显示出广泛的活化特征。令人惊讶的是，对促分裂原活化蛋白（MAP）激酶p44（ERK 1）和p42（ERK 2）的活化的分析表明，在用IL-5或PAF刺激后，ERK 2而不是ERK 1在人嗜酸性粒细胞中瞬时活化。活化动力学与细胞因子和趋化因子对p21 ras的活化相关，通过一种新的三磷酸鸟苷（GTP）负载测定。最后，使用p21 ras-ERK和PI 3 K信号通路的特异性抑制剂，证明了PI 3 K而不是p21 ras-ERK在IL-5和PAF引发的嗜酸性粒细胞中激活血清处理的酵母聚糖（STZ）介导的呼吸爆发中的作用。总之，这些数据表明，在人嗜酸性粒细胞，Th 2-衍生的细胞因子差异活化PI 3 K和MAP激酶信号转导途径，具有不同的功能后果，显示复杂的调节嗜酸性粒细胞效应功能。(C)1998年，美国血液学会。
Activation and recruitment of eosinophils in allergic inflammation is in part mediated by chemoattractants and T-helper 2 (Th2)-derived cytokines. However, little is known concerning the signal transduction mechanisms by which this activation occurs. We have investigated tyrosine kinase-mediated activation of phosphatidylinositol 3-kinase (PI3K) and compared this with the activation of the p21ras-ERK signaling pathway in human eosinophils. The related cytokines interleukin-3 (IL-3), IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF), all induced PI3K activity detected in antiphosphotyrosine immunoprecipitates. Furthermore, the chemoattractants platelet-activating factor (PAF), RANTES, and C5a were also able to induce phosphotyrosine-associated PI3K activity. Protein kinase B (PKB) is a downstream target of PI3K activation by growth factors. Induction of PKB phosphorylation in human eosinophils was transiently induced on activation with the cytokines IL-Q and IL-5, as well as the chemoattractants PAF, C5a, and RANTES showing a broad activation profile. Surprisingly, analysis of the activation of the mitogen-activated protein (MAP) kinases p44(ERK1) and p42(ERK2), showed that ERK2, but not ERK1, was transiently activated in human eosinophils after stimulation with IL-5 or PAF. Activation kinetics correlated with activation of p21ras by both cytokines and chemoattractants as measured by a novel assay for guanosine triphosphate (GTP)-loading. Finally, using specific inhibitors of both the p21ras-ERK and PI3K signaling pathways, a role was demonstrated for PI3K, but not p21ras-ERK, in activation of the serum-treated zymosan (STZ)-mediated respiratory burst in IL-5 and PAF-primed eosinophils. In summary, these data show that in human eosinophils, Th2-derived cytokines differentially activate both PI3K and MAP kinase signal transduction pathways with distinct functional consequences showing complex regulation of eosinophil effector functions. (C) 1998 by The American Society of Hematology.