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Differential Regulation of Prostaglandin E₂ and Thromboxane A₂ Production in Human Monocytes: Implications for the Use of Cyclooxygenase Inhibitors¹

Rheumatology Unit, Royal Adelaide Hospital, Adelaide, Australia

There is an autocrine relationship between eicosanoid and cytokine synthesis, with the ratio of prostaglandin E₂ (PGE₂)/thromboxane A₂ (TXA₂) being one of the determinants of the level of cytokine synthesis. In monocytes, cyclooxygenase type 1 (COX-1) activity appears to favor TXA₂ production and COX-2 activity appears to favor PGE₂ production. This has led to speculation regarding possible linkage of COX isozymes with PGE and TXA synthase. We have studied the kinetics of PGE₂ and TXA₂ synthesis under conditions that rely on COX-1 or -2 activity. With small amounts of endogenously generated prostaglandin H₂ (PGH₂), TXA₂ synthesis was greater than PGE₂. With greater amounts of endogenously generated PGH₂, PGE₂ synthesis was greater than TXA₂. Also, TXA synthase was saturated at lower substrate concentrations than PGE synthase. This pattern was observed irrespective of whether PGH₂ 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 PGE₂ than for TXA₂. 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 TXA₂ may have unwanted effects in long-term anti-inflammatory and anti-arthritic therapy.

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