Sphingosine inhibits phorbol ester-induced inflammation, ornithine decarboxylase activity, and activation of protein kinase C in mouse skin

Abstract

Tumor promoting phorbol esters, such as 12-0-tetradecanoylphorbol-13-acetate (TPA), when applied topically to mouse skin cause inflammation and hyperplasia. The major cellular phorbol ester receptor is a calcium and phospholipid dependent protein kinase, protein kinase C (PK-C). PK-C is directly activated by TPA and most of the responses of cells to TPA appear to be mediated by PK-C. This suggests that PK-C may play a key role as a mediator of inflammation and growth in TPA treated mouse skin. Sphingosine has been reported to be a potent inhibitor of PK-C in vitro and in intact leukocytes. We therefore have investigated the effects of sphingosine upon TPA-induced inflammation, hyperplasia, induction of ornithine decarboxylase (ODC) activity and ODC mRNA, and activation of PK-C in mouse skin. The results demonstrate that sphingosine is a potent inhibitor of all of the TPA-induced responses examined. These data are compatible with the hypothesis that PK-C is a major mediator of the phorbol ester response in mouse skin. Furthermore, PK-C inhibitors may have therapeutic potential in inflammatory skin diseases such as psoriasis.