Stromal cell-derived factor-1 and macrophage-derived chemokine: 2 chemokines that activate platelets.
Platelets play roles in both thrombosis and inflammation, and chemokines that are released at sites of inflammation could potentially activate platelets. Among the chemokine receptors expressed on platelets, the CXCR4 is the receptor for chemokine stromal cell-derived factor-1 (SDF-1), and the CCR4 is the receptor for macrophage-derived chemokine (MDC). Of the chemokines tested, SDF-1 and MDC were the only 2 that activated platelets. Both are weak agonists, but they enhanced response to low-dose adenosine 5'-diphosphate (ADP), epinephrine, or serotonin. When SDF-1 and MDC were added together, full and brisk platelet aggregation occurred. Platelet activation by these 2 chemokines appears to involve distinct pathways: SDF-1 inhibited an increase in cyclic adenosine monophosphate (cAMP) following prostaglandin (PG) I(2), while MDC had no effect. In contrast, MDC, but not SDF-1, lead to Ca(++) mobilization by platelets. Further, second-wave aggregation induced by MDC in platelet-rich plasma was inhibited by aspirin, ADP scavenger creatine phosphate/creative phosphokinase (CP/CPK), and ARL-66096, an antagonist of the ADP P2T(AC) receptor involved in adenylyl cyclase inhibition. But the aggregation was not affected by A3P5PS, an inhibitor of the ADP P2Y receptor. SDF-1-induced aggregation was inhibited by aspirin, but it was only slightly affected by CP/CPK, ARL-66096, or A3P5PS. Finally, the presence of chemokines in platelets was determined. Reverse transcriptase-polymerase chain reaction studies with platelet RNA did not detect the presence of SDF-1 or MDC. In summary, SDF-1 and MDC are platelet agonists that activate distinct intracellular pathways. Their importance in the development of thrombosis at sites of inflammation needs to be further evaluated.
Kowalska
M A
MA
Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. kowalska@email.chop.edu
Ratajczak
M Z
MZ
Majka
M
M
Jin
J
J
Kunapuli
S
S
Brass
L
L
Poncz
M
M
D000199:Actins / Q000097:blood / Q000235:genetics; D000244:Adenosine Diphosphate / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000097:blood; D054377:Chemokine CXCL12; D054426:Chemokine CXCL2; D018925:Chemokines / Q000097:blood / Q000235:genetics / Q000494:pharmacology*; D019743:Chemokines, CXC / Q000494:pharmacology*; D000242:Cyclic AMP / Q000097:blood; D003600:Cytosol / Q000378:metabolism; D004357:Drug Synergism; D004837:Epinephrine / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D015539:Platelet Activation / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics; D054398:Receptors, CCR4; D019707:Receptors, Chemokine / Q000187:drug effects / Q000235:genetics; D012701:Serotonin / Q000494:pharmacology; D017154:Stromal Cells / Q000502:physiology; D013929:Thromboxane B2 / Q000097:blood; D014158:Transcription, Genetic
D000199:Actins; C515354:CCR4 protein, human; C515255:CXCL12 protein, human; C515355:Ccr4 protein, mouse; D054377:Chemokine CXCL12; D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; C404915:Cxcl2 protein, mouse; D012333:RNA, Messenger; D054398:Receptors, CCR4; D019707:Receptors, Chemokine; D012701:Serotonin; D013929:Thromboxane B2; D000244:Adenosine Diphosphate; D000242:Cyclic AMP; D002118:Calcium; D004837:Epinephrine