Phospholipase A2 inhibitors regulate the proliferation of normal uterine cells

The effects of inhibitors of phospholipase A2, cyclooxygenase, lipoxygenase and cytochrome P450 activity on the proliferation of normal rat uterine stromal cells (UIII) were studied. At non-cytotoxic doses, inhibitors of cyclooxygenase, lipoxygenase and cytochrome P450 activity had no effect; UIII cells did not lose their ability to synthesize and secrete arachidonic acid metabolites, mainly prostaglandin I2 and prostaglandin E2, after successive passages. Inhibition of prostaglandin production did not affect their proliferation. In contrast, phospholipase A2 inhibitors significantly reduced UIII cell proliferation in a reversible and dose-dependent manner. Aristolochic acid was the most potent inhibitor with an IC50 of 0.3 mumol/l on day 7 of culture. Moreover, low doses of arachidonic acid stimulated UIII cell proliferation. Thus the proliferation of normal uterine stromal cells appears to be independent of arachidonic acid oxygenated metabolites, contrary to what is observed in tumor cells, but requires an intact phospholipase A2 pathway.