Differential regulation of prostaglandin E2 and thromboxane A2 production in human monocytes:: Implications for the use of cyclooxygenase inhibitors

There is an autocrine relationship between eicosanoid and cytokine synthesis, with the ratio of prostaglandin E-2 (PGE(2))/thromboxane A(2) (TXA(2)) being one of the determinants of the level of cytokine synthesis. In monocytes, cyclooxygenase type 1 (COX-1) activity appears to favor TXA(2) production and COX-2 activity appears to favor PGE(2) production. This has led to speculation regarding possible linkage of COX isozymes with PGE and TXA synthase, We have studied the kinetics of PGE(2) and TXA(2) synthesis under conditions that rely on COX-1 or -2 activity. With small amounts of endogenously generated prostaglandin H-2 (PGH(2)), TXA(2) synthesis was greater than PGE(2). With greater amounts of endogenously generated PGH(2), PGE(2) synthesis was greater than TXA(2.), Also, TXA synthase was saturated at lower substrate concentrations than PGE synthase, This pattern was observed irrespective of whether PGH(2) was produced by COX-1 or COX-2 or whether it was added directly, Furthermore, the inhibition of eicosanoid production by the action of nonsteroidal anti-inflammatory drugs or by the prevention of COX-2 induction with the p38 mitogen-activated protein kinase inhibitor SKF86002 was greater for PGE(2) than for TXA(2). It is proposed that different kinetics of PGE synthase and TXA synthase account for the patterns of production of these eicosanoids in monocytes under a variety of experimental conditions. These properties provide an alternative explanation to notional linkage or compartmentalization of COX-1 or -2 with the respective terminal synthases and that therapeutically induced changes in eicosanoid ratios toward predominance of TXA(2) may have unwanted effects in long-term anti-inflammatory and anti-arthritic therapy.