title: Thromboxane A(2) promotes soluble CD40 ligand release from human platelets.
abstract: 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.
authors.affiliation: Department of Neurosurgery, Graduate School of Medicine, Gifu University, Gifu, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Enomoto
authors.forename: Seiji
authors.initials: S
authors.lastname: Adachi
authors.forename: Rie
authors.initials: R
authors.lastname: Matsushima-Nishiwaki
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Doi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Niwa
authors.forename: Shigeru
authors.initials: S
authors.lastname: Akamatsu
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Tokuda
authors.forename: Shinji
authors.initials: S
authors.lastname: Ogura
authors.forename: Shinichi
authors.initials: S
authors.lastname: Yoshimura
authors.forename: Toru
authors.initials: T
authors.lastname: Iwama
authors.forename: Osamu
authors.initials: O
authors.lastname: Kozawa
mesh_terms: 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
chemical_list: 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