Role of prostaglandin H synthase-2-mediated conversion of arachidonic acid in controlling 3T6 fibroblast growth.

The specific role(s) of arachidonic acid (AA) and its metabolites in the signaling pathways that regulated fibroblast growth was studied. A Western blot analysis demonstrated that prostaglandin H synthase-2 (PGHS-2) was expressed by 3T6 fibroblast cultures in RPMI 1640 supplemented with fetal calf serum (10%). Dexamethasone, which inhibits AA release and PGHS-2 expression, significantly reduced cell proliferation. Ketoprofen, a dual cyclooxygenase inhibitor, and CGP-28238, a specific PGHS-2 inhibitor, reduced fibroblast proliferation in a dose-dependent manner. These drugs also reduced [3H]thymidine incorporation into the DNA of fibroblasts. These effects were correlated with a decrease in prostaglandin (PG) E2 levels in the cell medium. However, piroxicam at doses that selectively inhibit PGHS-1 did not have a significant effect on fibroblast proliferation. Finally, we showed that the antiproliferative effect of dexamethasone and PGHS-2 inhibitors was significantly antagonized when PGE2 was added to the culture medium. Our results suggest that PGHS-2 and prostaglandins such as PGE2 might play an important role in the regulation of 3T6 fibroblast growth stimulated by growth factors of serum.