Tunjungputri Rahajeng N, van der Ven Andre J, Riksen Niels, Rongen Gerard, Tacke Sabine, van den Berg T N A, Fijnheer Rob, Gomes Marc E, Dinarello Charles A, van de Veerdonk Frank L, Gasem M Hussein, Netea Mihai G, Joosten Leo A B, de Groot Philip G, de Mast Quirijn
Rahajeng Tunjungputri, MD, Department of Internal Medicine (463), Radboud university medical center, PO Box 9101, 6500 HB Nijmegen, The Netherlands, Tel: +31 24 3618822, Fax: +31 24 3566336, E-mail:
Thromb Haemost. 2015 May;113(5):1035-45. doi: 10.1160/TH14-07-0579. Epub 2015 Feb 26.
Platelets and platelet-monocyte interaction play an important role in inflammation. Both pro- and anti-inflammatory effects of platelet inhibition have been reported in animal models. This study aimed to investigate the effect of platelets and platelet inhibition by the new P2Y12 receptor antagonist ticagrelor on monocyte function, as assessed by cytokine responses to Toll-like Receptor (TLR) ligands. In a set of in vitro experiments, peripheral blood mononuclear cells (PBMC) incubated with the TLR2 ligand Pam3CSK4 produced less cytokines in the presence of platelets, whereas platelets increased the production of cytokines when PBMC were exposed to TLR4 ligand lipopolysaccharide (LPS). These effects of platelets were dependent on direct platelet-leukocyte aggregation and for the Pam3CSK4-induced response, on phagocytosis of platelets by monocytes. In a double blind, placebo-controlled crossover trial in healthy volunteers, a single oral dosage of 180 mg ticagrelor reduced platelet-monocyte complex (PMC) formation. This was associated with an increase in pro-inflammatory cytokines in blood exposed to Pam3CSK4, but a decrease in these cytokines in blood exposed to LPS. These findings show that platelets differentially modulate TLR2- and TLR4-mediated cytokine responses of PBMC. Through inhibition of platelet-leukocyte interaction, P2Y12 receptor antagonists may either exert a pro- or anti-inflammatory effect during infections depending on the TLR primarily involved.
血小板和血小板 - 单核细胞相互作用在炎症中起重要作用。在动物模型中已报道了血小板抑制的促炎和抗炎作用。本研究旨在通过对Toll样受体（TLR）配体的细胞因子反应评估，研究血小板及新型P2Y12受体拮抗剂替格瑞洛对单核细胞功能的抑制作用。在一组体外实验中，与TLR2配体Pam3CSK4孵育的外周血单个核细胞（PBMC）在有血小板存在的情况下产生的细胞因子较少，而当PBMC暴露于TLR4配体脂多糖（LPS）时，血小板会增加细胞因子的产生。血小板的这些作用取决于血小板与白细胞的直接聚集，对于Pam3CSK4诱导的反应，还取决于单核细胞对血小板的吞噬作用。在一项针对健康志愿者的双盲、安慰剂对照交叉试验中，单次口服180 mg替格瑞洛可减少血小板 - 单核细胞复合物（PMC）的形成。这与暴露于Pam3CSK4的血液中促炎细胞因子增加有关，但与暴露于LPS的血液中这些细胞因子减少有关。这些发现表明，血小板可差异性地调节PBMC的TLR2和TLR4介导的细胞因子反应。通过抑制血小板 - 白细胞相互作用，P2Y12受体拮抗剂在感染期间可能根据主要涉及的TLR发挥促炎或抗炎作用。
