Differential regulation of prostaglandin E-2 and thromboxane A(2) production in human monocytes: Implications for the use of cyclooxygenase inhibitors

There is an autocrine relationship between eicosanoid and cytokine synthesi s, with the ratio of prostaglandin E-2 (PGE(2))/thromboxane A(2) (TXA(2)) b eing one of the determinants of the level of cytokine synthesis. In monocyt es, cyclooxygenase type 1 (COX-1) activity appears to favor TXA(2) producti on and COX-2 activity appears to favor PGE(2) production. This has led to s peculation regarding possible linkage of COX isozymes with PGE and TXA synt hase, We have studied the kinetics of PGE(2) and TXA(2) synthesis under con ditions that rely on COX-1 or -2 activity. With small amounts of endogenous ly generated prostaglandin H-2 (PGH(2)), TXA(2) synthesis was greater than PGE(2). With greater amounts of endogenously generated PGH(2), PGE(2) synth esis was greater than TXA(2.), Also, TXA synthase was saturated at lower su bstrate concentrations than PGE synthase, This pattern was observed irrespe ctive of whether PGH(2) was produced by COX-1 or COX-2 or whether it was ad ded directly, Furthermore, the inhibition of eicosanoid production by the a ction 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 kine tics of PGE synthase and TXA synthase account for the patterns of productio n of these eicosanoids in monocytes under a variety of experimental conditi ons. These properties provide an alternative explanation to notional linkag e or compartmentalization of COX-1 or -2 with the respective terminal synth ases and that therapeutically induced changes in eicosanoid ratios toward p redominance of TXA(2) may have unwanted effects in long-term anti-inflammat ory and anti-arthritic therapy.