title: Differential response of platelets to chemokines: RANTES non-competitively inhibits stimulatory effect of SDF-1 alpha.
abstract: BACKGROUND
  Among the chemokines related to CXC and CC receptor groups and released from platelets, leukocytes and endothelial cells, SDF-1, TARC and MDC have been found to be platelet agonists. Platelets do not contain SDF-1 alpha. In contrast, RANTES is constitutively present in platelet alpha-granules and released upon platelet activation.
  
  
  OBJECTIVE
  To study a possible role of RANTES as a modulator of SDF-1 alpha effect on platelets, in relation to CXCR4 and various CC receptors.
  
  
  METHODS
  CXCR-4 (CXCL12) receptor expression and platelet activation were evaluated by flow cytometry, platelet deposition was studied by cone and plate(let) analyzer, and platelet aggregation by turbidometric aggregometry.
  
  
  RESULTS
  Flow cytometry studies revealed similar expression of CXCR-4, the specific receptor of SDF-1 alpha on intact, inactivated, and activated platelets. Preincubation of platelets with RANTES affected neither CXCR-4 expression, nor SDF-1 alpha binding to the platelet membrane. In the presence of fibrinogen, SDF-1 alpha activated gel-filtered platelets. RANTES did not activate platelets, but substantially (by 70%) inhibited SDF-1 alpha-induced fibrinogen binding. Similarly, RANTES abrogated the promoting effect of SDF-1 alpha on whole blood platelet adhesion to endothelial cell monolayer under venous flow conditions. In platelet-rich plasma, RANTES moderately inhibited SDF-1 alpha-induced platelet aggregation, while it did not affect aggregation induced by thrombin-receptor activation peptide, adenosine diphosphate, or phorbol 12-myristate 13-acetate. A synergistic inhibitory effect of RANTES and prostaglandin E1 used at subthreshold concentrations, on SDF-1 alpha-induced aggregation and SDF-1 alpha-induced fibrinogen binding to platelets was observed, which may suggest involvement of RANTES in a cAMP-dependent signal transduction pathway.
  
  
  CONCLUSIONS
  RANTES non-competitively inhibits activation of platelets by SDF-1 alpha, and thus may play a regulatory role in platelet response to inflammation.
authors.affiliation: Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel-Hashomer, Israel. borshenk@sheba.health.gov.il
authors.forename: B
authors.initials: B
authors.lastname: Shenkman
authors.forename: A
authors.initials: A
authors.lastname: Brill
authors.forename: G
authors.initials: G
authors.lastname: Brill
authors.forename: O
authors.initials: O
authors.lastname: Lider
authors.forename: N
authors.initials: N
authors.lastname: Savion
authors.forename: D
authors.initials: D
authors.lastname: Varon
mesh_terms: D001792:Blood Platelets / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000494:pharmacology*; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology*; D004347:Drug Interactions; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D015539:Platelet Activation / Q000187:drug effects; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000097:blood
chemical_list: C515255:CXCL12 protein, human; D018946:Chemokine CCL5; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D019718:Receptors, CXCR4