Glucocorticoids block the induced secretion of prostaglandins in a variety of biological contexts. We have identified a primary response gene, TIS10, which encodes a mitogen-inducible prostaglandin synthase/cyclooxygenase in Swiss 3T3 cells. TIS10 is distinct from prostaglandin synthase/cyclooxygenase. (EC 1.14.99.1), previously cloned from mouse, man, and sheep. Dexamethasone blocks prostaglandin E2 synthesis by 3T3 cells in response to tetradecanoylphorbol acetate. Dexamethasone also blocks both phorbol ester- and forskolin-induced TIS10 mRNA accumulation. In contrast, phorbol esters, forskolin, and dexamethasone have little or no effect on the levels of prostaglandin synthase/cyclooxygenase mRNA in 3T3 cells. Moreover, dexamethasone does not inhibit induction of TIS8/egr-1, another primary response gene. Inhibition of the synthesis of TIS10 prostaglandin synthase/cyclooxygenase may be a principal mechanism by which glucocorticoids block prostaglandin synthesis and secretion.