Comparison of tumour promoter-induced prostaglandin E2 release in human and rat keratinocytes.

Abstract

Prostaglandin E2 (PGE2) is associated with phorbol ester-induced skin irritation and tumour promotion, but the mechanism of action is not fully understood and the role of keratinocyte-derived PGE2 is unclear. PGE2 was recently reported to modulate keratinocyte differentiation and phorbol-12-myristate-13-acetate (PMA), the most extensively studied phorbol ester tumour promoter in mouse skin, was shown to stimulate PGE2 release in human keratinocytes. Preliminary data on PGE2 release induced by PMA, mezerein, anthralin, sodium dodecyl sulphate and acetic acid in human keratinocyte cultures is compared to their response in rat keratinocytes. Our data confirms a previously published report on stimulation of PGE2 release by PMA in human keratinocytes and also demonstrates a difference in the magnitude of the PMA- and mezerein-induced response between human and rat keratinocyte cultures at non-cytotoxic concentrations. Cytotoxicity was evaluated by the Neutral Red uptake assay and a concentration that reduced cell viability to 50% of control was selected as a maximum concentration for subsequent measurement of PGE2 release. In contrast, anthralin, sodium dodecyl sulphate and acetic acid induced a similar degree of PGE2 release in human and rat keratinocyte cultures, but release was specifically associated with a cytotoxic response. Non-cytotoxic concentrations of these three chemicals did not stimulate release of PGE2. This study illustrates that PGE2 dose-response curves may reflect different mechanisms of action that may be intimately associated with skin irritant and tumour promoting activity. The data indicates a possible species difference in keratinocyte response to PMA and mezerein. The important value of keratinocyte cultures for mechanistic studies of tumour promotion and skin irritation is highlighted and further research is warranted into the potential role of intracellular pathways, which modulate keratinocyte differentiation and proliferation, in these processes.