Arachidonic acid is preferentially metabolized by cyclooxygenase-2 to prostacyclin and prostaglandin E2

The two cyclooxygenase isoforms, cyclooxygenase-1 and cyclooxygenase-2, both metabolize arachidonic acid to prostaglandin H-2, which is subsequently processed by downstream enzymes to the various prostanoids. In the present study, we asked if the two isoforms differ in the profile of prostanoids that ultimately arise from their action on arachidonic acid. Resident peritoneal macrophages contained only cyclooxygenase-1 and synthesized (from either endogenous or exogenous arachidonic acid) a balance of four major prostanoids: prostacyclin, thromboxane A(2), prostaglandin D-2, and 12-hydroxyheptadecatrienoic acid. Prostaglandin E-2 was a minor fifth product, although these cells efficiently converted exogenous prostaglandin H-2 to prostaglandin E-2. By contrast, induction of cyclooxygenase-a with lipopolysaccharide resulted in the preferential production of prostacyclin and prostaglandin E-2. This shift in product profile was accentuated if cyclooxygenase-1 was permanently inactivated with aspirin before cyclooxygenase-2 induction. The conversion of exogenous prostaglandin H-2 to prostaglandin E-2 was only modestly increased by lipopolysaccharide treatment. Thus, cyclooxygenase-a induction leads to a shift in arachidonic acid metabolism from the production of several prostanoids with diverse effects as mediated by cyclooxygenase-1 to the preferential synthesis of two prostanoids, prostacyclin and prostaglandin E-2, which evoke common effects at the cellular level.