Thromboxane A(2) promotes soluble CD40 ligand release from human platelets.
OBJECTIVE
The plasma level of soluble CD40 ligand (sCD40L), which induces pro-inflammatory and pro-atherogenic responses, is known to be elevated in atherosclerotic patients. In this study, we investigated the mechanism of sCD40L release from human platelets, focusing on the involvement of thromboxane (TX) A(2).


METHODS
We measured sCD40L release and TXA(2) production induced by ristocetin, an activator of GPIb/IX/V, from human platelets in vitro. Moreover, plasma sCD40L and TXA(2) levels in the 10 patients with severe carotid artery stenosis who were not taking any anti-platelet medicines were measured and compared with those obtained from non-atherosclerotic controls.


RESULTS
Ristocetin significantly promoted sCD40L release and TXA(2) generation from platelets in vitro. Aspirin and SC-560, a cyclooxygenase-1 inhibitor, suppressed the ristocetin-induced sCD40L release from platelets in parallel with TXA(2) production. Ozagrel, a TXA(2) synthase inhibitor and PTXA(2), a thromboxane receptor (TP) antagonist also suppressed sCD40L release. U46619, a TP agonist, reversed the suppressive effect of aspirin on sCD40L release. In vivo, plasma levels of sCD40L and TXA(2) in the patients were significantly higher than those in controls. Elevated plasma levels of TXA(2) and sCD40L in the patients were markedly diminished after 7 days of 100mg aspirin administration.


CONCLUSIONS
These results strongly suggest that GPIb/IX/V activation induces sCD40L release via TXA(2) from human platelets, and that sCD40L release via TXA(2) generation from platelets in atherosclerotic patients are up-regulated.
Enomoto
Yukiko
Y
Department of Neurosurgery, Graduate School of Medicine, Gifu University, Gifu, Japan.
Adachi
Seiji
S
Matsushima-Nishiwaki
Rie
R
Doi
Tomoaki
T
Niwa
Masayuki
M
Akamatsu
Shigeru
S
Tokuda
Haruhiko
H
Ogura
Shinji
S
Yoshimura
Shinichi
S
Iwama
Toru
T
Kozawa
Osamu
O
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000368:Aged; D001241:Aspirin / Q000494:pharmacology; D050197:Atherosclerosis / Q000097:blood; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D023201:CD40 Ligand / Q000097:blood*; D002340:Carotid Artery Diseases / Q000097:blood; D005260:Female; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D008689:Methacrylates / Q000494:pharmacology; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D011720:Pyrazoles; D012310:Ristocetin / Q000494:pharmacology; D013928:Thromboxane A2 / Q000096:biosynthesis* / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D008689:Methacrylates; D011720:Pyrazoles; C115461:SC 560; D012310:Ristocetin; D023201:CD40 Ligand; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C034364:ozagrel; D001241:Aspirin