title: Differential effects of platelets and platelet inhibition by ticagrelor on TLR2- and TLR4-mediated inflammatory responses.
abstract: 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.
authors.affiliation: 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: Rahajeng.Tunjungputri@radboudumc.nl.
authors.forename: Rahajeng N
authors.initials: RN
authors.lastname: Tunjungputri
authors.forename: Andre J
authors.initials: AJ
authors.lastname: van der Ven
authors.forename: Niels
authors.initials: N
authors.lastname: Riksen
authors.forename: Gerard
authors.initials: G
authors.lastname: Rongen
authors.forename: Sabine
authors.initials: S
authors.lastname: Tacke
authors.forename: T N A
authors.initials: TN
authors.lastname: van den Berg
authors.forename: Rob
authors.initials: R
authors.lastname: Fijnheer
authors.forename: Marc E
authors.initials: ME
authors.lastname: Gomes
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Frank L
authors.initials: FL
authors.lastname: van de Veerdonk
authors.forename: M Hussein
authors.initials: MH
authors.lastname: Gasem
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Philip G
authors.initials: PG
authors.lastname: de Groot
authors.forename: Quirijn
authors.initials: Q
authors.lastname: de Mast
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000244:Adenosine Diphosphate / Q000737:chemistry; D000328:Adult; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects*; D018592:Cross-Over Studies; D016207:Cytokines / Q000378:metabolism; D004311:Double-Blind Method; D006801:Humans; D007249:Inflammation; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008024:Ligands; D008070:Lipopolysaccharides / Q000737:chemistry; D008297:Male; D009000:Monocytes / Q000166:cytology; D010587:Phagocytosis; D015539:Platelet Activation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use; D010979:Platelet Function Tests; D012333:RNA, Messenger / Q000378:metabolism; D000077486:Ticagrelor; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D055815:Young Adult
chemical_list: D016207:Cytokines; D008024:Ligands; D008070:Lipopolysaccharides; D010975:Platelet Aggregation Inhibitors; D012333:RNA, Messenger; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D000244:Adenosine Diphosphate; D000077486:Ticagrelor; D000241:Adenosine
keywords: Platelets; Toll-like receptor; inflammation; platelet-monocyte complex; ticagrelor