Human airway eosinophils respond to chemoattractants with greater eosinophil-derived neurotoxin release, adherence to fibronectin, and activation of the Ras-ERK pathway when compared with blood eosinophils.
Human airway eosinophils respond to chemoattractants with greater eosinophil-derived neurotoxin release, adherence to fibronectin, and activation of the Ras-ERK pathway when compared with blood eosinophils.
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DOI：
10.4049/jimmunol.0900634
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发表时间：
2010-06-15
期刊：
影响因子：
--
通讯作者：
Bertics PJ
中科院分区：
文献类型：
--
作者：
Bates ME;Sedgwick JB;Zhu Y;Liu LY;Heuser RG;Jarjour NN;Kita H;Bertics PJ
离体暴露于造血细胞因子（例如，IL-5或GM-CSF）随后通过称为引发的过程显示出对许多化学引诱物（如趋化因子、PAF或FMLP）的增强的应答性。气道嗜酸性粒细胞，获得支气管肺泡灌洗后，节段性抗原的挑战，也表现出增强的反应性选择的化学引诱剂，这表明他们是在细胞运输过程中从血液到气道。早期的工作表明，在体外IL-5引发后，化学引诱物刺激ERK 1和ERK 2的更大活化，从而揭示了ERK 1/ERK 2活性可以是在这些情况下引发的分子读数。由于很少有研究已经检查了细胞内的机制调节启动，因为它涉及到人类气道嗜酸性粒细胞，我们评估了血液和气道嗜酸性粒细胞的反应性，以化学引诱剂（FMLP，PAF，CCL 11，CCL 5，CXCL 8）方面的脱粒，粘附纤连蛋白，或Ras-ERK信号级联激活。与血液嗜酸性粒细胞相比，气道嗜酸性粒细胞表现出更大的FMLP刺激的EDN释放以及增强FMLP和CCL 11刺激的粘附纤连蛋白。在气道嗜酸性粒细胞中，与基线相比，FMLP、CCL 11和CCL 5刺激Ras或ERK 1/ERK 2更大的活化。在IL-5引发后，FMLP在血液嗜酸性粒细胞中的Ras活化也增强。这些研究与过敏原激发后IL-5或相关细胞因子对嗜酸性粒细胞的体内致敏模型一致，并进一步证明了致敏在嗜酸性粒细胞的化学引诱物刺激反应中的关键作用。这些数据还表明了Ras-ERK信号通路对气道中嗜酸性粒细胞对化学引诱物的反应的调节的重要性。
Human blood eosinophils exposed ex vivo to hematopoietic cytokines (e.g., IL-5 or GM-CSF) subsequently display enhanced responsiveness to numerous chemoattractants, such as chemokines, PAF or FMLP, through a process known as priming. Airway eosinophils, obtained by bronchoalveolar lavage after segmental antigen challenge, also exhibit enhanced responsiveness to selected chemoattractants, suggesting that they are primed during cell trafficking from the blood to the airway. Earlier work has shown that chemoattractants stimulate greater activation of ERK1 and ERK2 following IL-5-priming in vitro, thus revealing that ERK1/ERK2 activity can be a molecular readout of priming under these circumstances. Because few studies have examined the intracellular mechanisms regulating priming as it relates to human airway eosinophils, we evaluated the responsiveness of blood and airway eosinophils to chemoattractants (FMLP, PAF, CCL11, CCL5, CXCL8) with respect to degranulation, adherence to fibronectin, or Ras-ERK signaling cascade activation. When compared to blood eosinophils, airway eosinophils exhibited greater FMLP-stimulated EDN release as well as augmented FMLP- and CCL11-stimulated adherence to fibronectin. In airway eosinophils, FMLP, CCL11 and CCL5 stimulated greater activation of Ras or ERK1/ERK2 when compared to baseline. Ras activation by FMLP in blood eosinophils was also enhanced following IL-5-priming. These studies are consistent with a model of in vivo priming of eosinophils by IL-5 or related cytokines following allergen challenge, and further demonstrate the key role of priming in the chemoattractant-stimulated responses of eosinophils. The data also demonstrate the importance of the Ras-ERK signaling pathway to the regulation of eosinophil responses to chemoattractants in the airway.
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