Differential effects of platelets and platelet inhibition by ticagrelor on TLR2- and TLR4-mediated inflammatory responses

Thrombosis and Haemostasis - Tập 113 Số 05 - Trang 1035-1045 - 2015
Rahajeng N. Tunjungputri1, André van der Ven, Edwin A. Deitch, Gerard A. Rongen, Sabine Tacke, T.N.A. van den Berg, Rob Fijnheer, Marc E Gomes, Charles A. Dinarello, Frank L. van de Veerdonk, Muhammad Hussein Gasem, Mihai G. Netea, Leo A. B. Joosten, Philip G. de Groot, Quirijn de Mast1
1Rahajeng 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: [email protected].

Tóm tắt

SummaryPlatelets 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.

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Tài liệu tham khảo

10.1038/nri2956

10.1161/CIRCRESAHA.113.300512

10.1172/JCI118575

10.1172/JCI117921

10.1097/00062752-200303000-00009

10.1055/s-2007-969023

10.1159/000339857

10.1067/mcp.2003.13

10.1016/j.jacc.2003.10.071

10.3109/09537104.2013.842965

10.1097/SHK.0b013e3181f48987

10.1186/cc5187

Winning, 2009, Platelets, 20, 50, 10.1080/09537100802503368

10.1371/journal.pone.0026035

10.1128/IAI.69.3.1477-1482.2001

10.1097/QAD.0000000000000415

van Bladel ER, Laarhoven AG, van der Heijden LB, et al. Functional platelet defects in children with severe chronic ITP as tested with two novel assays applicable for low platelet counts. Blood 2014; Epub ahead of print

10.1182/blood-2011-12-396440

Kirkpatrick, 1980, Thromb Haemost, 42, 1483

10.1001/archinternmed.2009.42

10.1007/s11239-012-0833-4

10.1172/JCI27209.

10.1189/jlb.0708400

10.1371/journal.pone.0050746

10.1128/IAI.01455-08

10.4049/jimmunol.1201103

10.1182/blood-2005-06-2202

Nylander, 2013, J Thromb Haemost, 11, 1867, 10.1111/jth.12360

Eltzschig, 2013, N Engl J Med, 368, 1260

10.1111/1755-5922.12021

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Thông tin xuất bản

Thrombosis and Haemostasis

Tập 113 Số 05

1035-1045

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