Abi-Younes S, Si-Tahar M, Luster A D
Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
Thromb Res. 2001 Feb 15;101(4):279-89. doi: 10.1016/s0049-3848(00)00402-3.
While chemokines have received considerable attention for their role in leukocyte chemotaxis, their effects on platelets have not been well described. We found that two CC chemokine receptor 4 (CCR4) ligands, macrophage-derived chemokine (MDC) and thymus and activation-regulated chemokine (TARC) induce concentration-dependent platelet aggregation and calcium flux. Flow cytometric analysis revealed the expression of CCR4 on platelets and a monoclonal antibody (mAb) to CCR4 inhibited MDC- and TARC-induced platelet aggregation, confirming that this effect is mediated through their common receptor CCR4. MDC fully desensitized TARC-induced calcium mobilization in platelets, while TARC was unable to completely desensitize a subsequent MDC response, which is similar to observations made in Th2 CD4(+) lymphocytes and CCR4-transfected cells. Aspirin (ASA) treatment of platelets allowed reversible primary aggregation but inhibited irreversible complete aggregation, suggesting that MDC- and TARC-induced full platelet aggregation is dependent on cyclooxygenase metabolites of arachidonic acid. MDC and TARC were unable to induce platelet aggregation and platelet secretion in washed human platelets, even though they induced a calcium flux, suggesting that plasma components are required for MDC- and TARC-induced platelet aggregation. Since Th2-type cytokines induce the release of MDC and TARC from cells and the expression of these chemokines is increased in Th2-type inflammation, we hypothesize that MDC and TARC may play a role in platelet activation seen in Th2 diseases, such as asthma and atopic dermatitis.
尽管趋化因子在白细胞趋化作用中的角色已受到广泛关注，但其对血小板的影响尚未得到充分描述。我们发现两种CC趋化因子受体4（CCR4）配体，巨噬细胞衍生趋化因子（MDC）和胸腺与激活调节趋化因子（TARC）可诱导浓度依赖性的血小板聚集和钙内流。流式细胞术分析显示血小板上存在CCR4表达，且一种针对CCR4的单克隆抗体（mAb）可抑制MDC和TARC诱导的血小板聚集，证实该效应是通过它们的共同受体CCR4介导的。MDC可使TARC诱导的血小板钙动员完全脱敏，而TARC不能完全使随后的MDC反应脱敏，这与在Th2 CD4(+)淋巴细胞和CCR4转染细胞中的观察结果相似。阿司匹林（ASA）处理血小板可使可逆的初级聚集发生，但抑制不可逆的完全聚集，提示MDC和TARC诱导的完全血小板聚集依赖于花生四烯酸的环氧化酶代谢产物。MDC和TARC不能在洗涤后的人血小板中诱导血小板聚集和血小板分泌，尽管它们可诱导钙内流，提示血浆成分是MDC和TARC诱导血小板聚集所必需的。由于Th2型细胞因子可诱导细胞释放MDC和TARC，且这些趋化因子的表达在Th2型炎症中增加，我们推测MDC和TARC可能在Th2疾病（如哮喘和特应性皮炎）中所见的血小板激活中发挥作用。
