Possible involvement of chemokine-induced platelet activation in thrombophilic diathesis of antiphospholipid syndrome.
Among the heterogeneous antiphospholipid antibodies, many studies suggest that those directed to beta2-glycoprotein I (beta2GPI) are the major pathogenic antibodies in antiphospholipid syndrome (APS). They have been shown to activate the coagulation pathway via several mechanisms, activate platelets via thrombin formation, and suppress fibrinolysis. Additionally, we propose another possible mechanism that involves certain chemokines and results in platelet activation. This hypothesis is based on the observations that anti-beta2GPI antibodies stimulated monocytes to secrete inflammatory cytokines such as IL-1beta and TNF-alpha, which in turn stimulated vascular endothelial cells to express chemokines such as CX3CL1 and CCL5. CX3CL1 increased the ability of normal platelets to adhere to collagen at a high shear rate, while CCL5 induced platelet aggregation. Expression of tissue factor, IL-1beta, and TNF-alpha by monocytes stimulated with anti-beta2GPI antibodies, as well as CX3CL1 and CCL5 by vascular endothelial cells stimulated with IL-1beta or TNF-alpha were all suppressed by the NF-kappaB-specific inhibitor DHMEQ. These results suggest that the NF-kappaB pathway may be a potential therapeutic target relating to both the coagulation pathway and platelet activity.
Kubota
Tetsuo
T
Tokyo Medical and Dental University Graduate School of Health Care Sciences, Department of Microbiology and Immunology, Tokyo, Japan. tetsuo.kubota.mtec@tmd.ac.jp
Fukuya
Yasuko
Y
Hashimoto
Rieko
R
Kanda
Takashi
T
Suzuki
Hidenori
H
Okamura
Yosuke
Y
Nanki
Toshihiro
T
Miyasaka
Nobuyuki
N
Umezawa
Kazuo
K
D016736:Antiphospholipid Syndrome / Q000097:blood* / Q000276:immunology; D001323:Autoantibodies / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D054428:Chemokine CX3CL1 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D018925:Chemokines / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D003512:Cyclohexanones / Q000494:pharmacology; D004198:Disease Susceptibility; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism; D013927:Thrombosis / Q000276:immunology / Q000378:metabolism*; D053482:beta 2-Glycoprotein I / Q000276:immunology
D001323:Autoantibodies; D001549:Benzamides; D018946:Chemokine CCL5; D054428:Chemokine CX3CL1; D018925:Chemokines; D003512:Cyclohexanones; D053482:beta 2-Glycoprotein I; C464444:dehydroxymethylepoxyquinomicin; D013925:Thromboplastin