Modulation of keratinocyte proliferation in vitro by endogenous prostaglandin synthesis

To understand the relationship between the proliferation of epidermis and its arachidonic acid metabolism, we studied human keratinocytes grown in vitro at confluent or nonconfluent densities. Keratinocyte cultures incubated with [14C]arachidonic acid synthesized prostaglandin (PG)E2 PGD2, PGF2 alpha, and small quantities of 6-keto-F1 alpha. Nonconfluent cultures, however, synthesized fourfold more PGE2 than did confluent cultures. When proliferation was studied using [3H]thymidine incorporation into DNA, it was found that this increased synthesis of PGE2 was accompanied by a fourfold increase in the rate of proliferation. When PGE2 synthesis was inhibited by indomethacin, the rate of proliferation of nonconfluent cultures was decreased 40%, while the rate of proliferation of confluent cultures was unchanged. Addition of 1 ng/ml of PGE2, but not PGF2 alpha, PGD2, or a stable analog of PGI2 to the indomethacin-treated nonconfluent cultures restored the initial rate of proliferation. These results suggest that PGE2 is a growth-promoting autocoid for epidermis. The synthesis of PGE2 by epidermis may be enhanced in wound healing and disease states where epidermal continuity is disrupted.