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 100 mg aspirin administration. Conclusion 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.