Activation Via Multiple Signaling Pathways Induces Down-Regulation of Platelet-Activating Factor Receptors on Human B Lymphocytes1
Activation Via Multiple Signaling Pathways Induces Down-Regulation of Platelet-Activating Factor Receptors on Human B Lymphocytes1
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通过多种信号通路激活可诱导人 B 淋巴细胞上血小板激活因子受体的下调1
作者：
Q. Zhuang;Y. Bastien;B. Mazer
血小板活化因子受体（PAFR）已在B细胞系和原代人B细胞中被鉴定，但PAFR在B细胞活化过程中的调节尚未完全阐明。在本研究中，我们研究了B细胞活化对PAFR结合参数、PAFR mRNA和PAF触发的细胞内钙动员的影响。通过PAFR拮抗剂[3 H] WEB 2086的放射性配体结合试验测定，人B淋巴细胞系LA 350显示出高水平的PAFR（48，550 ± 4，310个位点/细胞）。用佛波醇12，13-二丁酸酯治疗引起PAFR结合的双相减少。蛋白激酶C抑制剂bisindolylmaleimide I（BIM）可抑制早期阶段，而BIM、蛋白酪氨酸激酶抑制剂genistein或丝裂原活化蛋白激酶/细胞外信号相关激酶抑制剂PD 98059则不能阻断晚期阶段。而广谱蛋白激酶抑制剂staurosporine可完全抑制晚期下调。离子霉素也减少了[3 H]WEB2086结合位点，而PDB和离子霉素的组合比单独使用任何一种药物诱导了更大的减少。抗IgM抗体交联B细胞受体也可诱导PAFR下调，染料木黄酮或PD 98059可消除这种作用，但BIM或星形孢菌素不能消除这种作用。在LA 350细胞和人扁桃体B细胞中，表面PAFR数量的减少与PAFR mRNA的减少密切相关，并且与细胞内钙动员减少所指示的对PAF的反应降低相关。这些数据表明，多种信号通路参与了B细胞活化和发育过程中PAFR表达的下调。
Platelet-activating factor receptor (PAFR) has been identified in B cell lines and primary human B cells, but the regulation of PAFR during B cell activation has not been completely elucidated. In the present study, we have investigated the effects of B cell activation on PAFR binding parameters, PAFR mRNA and PAF-triggered intracellular calcium mobilization. The human B lymphoid cell line LA350 was shown to exhibit high levels of PAFR (48,550 ± 4,310 sites/cell) as determined by radio-ligand binding assay with PAFR antagonist [3H]WEB2086. Treatment with phorbol 12,13-dibutyrate caused a biphasic reduction of PAFR binding. The early phase was inhibited by the protein kinase C inhibitor bisindolylmaleimide I (BIM), whereas the late phase was not blocked by BIM, protein tyrosine kinase inhibitor genistein, or the mitogen-activated protein kinase/extracellular signal-related kinase inhibitor PD98059. However, staurosporine, a broad-spectrum protein kinase inhibitor, completely inhibited the late phase down-regulation. Ionomycin also decreased [3H]WEB2086 binding sites, whereas the combination of PDB and ionomycin induced a greater reduction than either agent alone. Cross-linking of B cell receptor by anti-IgM Ab also induced down-regulation of PAFR, which was abolished by genistein or PD98059, but not by BIM or staurosporine. The decrease in surface PAFR number was closely paralleled by the reduction in PAFR mRNA both in LA350 cells and human tonsillar B cells, and was associated with decreased response to PAF indicated by decreased intracellular calcium mobilization. These data show that multiple signaling pathways are involved in down-regulating PAFR expression during B cell activation and development.
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DOI：
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DOI：
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期刊：
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DOI：
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