The role of platelet-derived growth factor receptor in eotaxin signaling of eosinophils
The role of platelet-derived growth factor receptor in eotaxin signaling of eosinophils
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DOI：
10.1159/000092708
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发表时间：
2006-01-01
影响因子：
2.8
通讯作者：
Ohta, K
中科院分区：
文献类型：
--
作者：
Adachi, T;Hanaka, S;Ohta, K
背景资料：受体酪氨酸激酶（RTK）如表皮生长因子受体（EGFR）和血小板衍生生长因子受体（PDGFR）能够在配体结合后引发激酶活性。在几种细胞中，RTK通过G蛋白偶联受体激活，而不依赖于配体-RTK相互作用。我们以前发现，EGFR是通过CC趋化因子受体3在支气管上皮细胞中的反式激活，这条途径是重要的丝裂原活化蛋白（MAP）激酶激活和细胞因子的生产。最近有人提出，高嗜酸性粒细胞综合征的结果融合酪氨酸激酶FIP 1 L1-PDGFRA。虽然PDGFR信号可能参与嗜酸性粒细胞功能，但具体细节仍不清楚。方法：采用Percoll和抗CD 16抗体包被的磁性微球纯化血嗜酸性粒细胞。RT-PCR检测PDGFR mRNA的表达。用嗜酸性粒细胞活化趋化因子刺激嗜酸性粒细胞后，用抗磷酸特异性MAP激酶抗体通过Western印迹法检测MAP激酶的磷酸化。使用Boyden小室研究了嗜酸性粒细胞趋化因子诱导的嗜酸性粒细胞趋化性。结果：8例供者中有4例嗜酸性粒细胞表达PDGFRP mRNA，而仅1例供者表达PDGFR α mRNA。PDGFR的蛋白表达也可在一些供体的嗜酸性粒细胞中检测到。AG 1295是PDGFR的特异性抑制剂，对表达PDGFRP mRNA的嗜酸性粒细胞中嗜酸性粒细胞活化趋化因子诱导的MAP激酶磷酸化具有剂量依赖性抑制作用。这些嗜酸性粒细胞的趋化性被AG 1295显著抑制（n = 3）。结论：我们的研究结果表明，PDGFR修改CCR 3-MAP激酶信号通路和趋化反应在一些捐助者。PDGFR的药理学靶向可能是治疗嗜酸性粒细胞疾病的新策略。版权所有（c）2006 S. Karger AG，巴塞尔。
Background: Receptor tyrosine kinases (RTKs) such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR) are capable of eliciting kinase activity after ligand binding. In several cells, RTKs are activated via the G-protein-coupled receptor independent of the ligand-RTK interaction. We have previously found that EGFR is transactivated via CC chemokine receptor 3 in bronchial epithelial cells and that this pathway is important for mitogen-activated protein (MAP) kinase activation and cytokine production. It has recently been suggested that hypereosinophilic syndrome results from the fusion tyrosine kinase FIP1L1-PDGFRA. Although it is possible that the PDGFR signal is involved in eosinophil function, the details are still unclear. Methods: Blood eosinophils were purified using Percoll and anti-CD16 antibody-coated magnetic beads. Expression of PDGFR mRNA was examined by RT-PCR. After stimulating eosinophils with eotaxin, the phosphorylation of MAP kinases was examined by Western blotting with the antiphosphospecific MAP kinase antibody. The eotaxin-induced eosinophil chemotaxis was studied using Boyden chambers. Results: Eosinophils expressed PDGFRP mRNA in 4 out of 8 donors, while PDGFR alpha mRNA was expressed in only 1 donor. Protein expression of PDGFR was also detectable in eosinophils from some donors. AG1295, a specific inhibitor of PDGFR, showed dose-dependent inhibition of eotaxin-induced MAP kinase phosphorylation in the eosinophils expressing PDGFRP mRNA. The chemotaxis of these eosinophils was significantly inhibited by AG1295 (n = 3). Conclusions: Our results suggest that PDGFR modifies the CCR3-MAP kinase signaling pathway and chemotactic response in some donors. The pharmacological targeting of PDGFR may be a new strategy to treat eosinophilic disorders. Copyright (c) 2006 S. Karger AG, Basel.