Effects of thromboxane A 2 on lymphocyte proliferation

Abstract

The main cyclooxygenase-dependent arachidonic acid derivatives produced by monocytes and macrophages have been shown to be thromboxane A 2 and prostaglandin E 2. The immunomodulatory effects of thromboxane A 2 were examined using a specific thromboxane synthase inhibitor (dazoxiben), a thromboxane A 2 analog (U46619), and a thromboxane A 2 receptor blocker (BM13.177). Dazoxiben inhibited lymphocyte proliferation in response to mitogens (PHA and OKT3), but also reoriented cyclic endoperoxide metabolism towards the production of prostaglandin E 2. Prostaglandin E 2 has been shown previously to inhibit mitogen-induced lymphocyte proliferation. U46619, a stable thromboxane A 2 analog, slightly enhanced lymphocyte responses to mitogens in the presence of dazoxiben and in the presence of a cyclooxygenase inhibitor (indomethacin). This occurred at concentrations of U46619 which are probably supraphysiological in view of the short half-life of natural thromboxane A 2. Finally, the thromboxane A 2 receptor blocker BM13.177 did not have any effect on mitogen-induced lymphocyte proliferation. It is concluded that thromboxane A 2 has no or minimal modulatory effects on lymphocyte proliferative responses to mitogens and that the effect of thromboxane A 2 synthase inhibition is rather due to reorientation of cyclic endoperoxide metabolism, resulting in increased prostaglandin E 2 production.