Thromboxane A2 promotes soluble CD40 ligand release from human platelets



      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) A2.


      We measured sCD40L release and TXA2 production induced by ristocetin, an activator of GPIb/IX/V, from human platelets in vitro. Moreover, plasma sCD40L and TXA2 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.


      Ristocetin significantly promoted sCD40L release and TXA2 generation from platelets in vitro. Aspirin and SC-560, a cyclooxygenase-1 inhibitor, suppressed the ristocetin-induced sCD40L release from platelets in parallel with TXA2 production. Ozagrel, a TXA2 synthase inhibitor and PTXA2, 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 TXA2 in the patients were significantly higher than those in controls. Elevated plasma levels of TXA2 and sCD40L in the patients were markedly diminished after 7 days of 100 mg aspirin administration.


      These results strongly suggest that GPIb/IX/V activation induces sCD40L release via TXA2 from human platelets, and that sCD40L release via TXA2 generation from platelets in atherosclerotic patients are up-regulated.


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