Keratinocyte differentiation is induced by cell-permeant ceramides and its proliferation is promoted by sphingosine

Ceramide and sphingosine have been suggested to be intracellular modulators of cell growth and differentiation. The effects of these sphingolipids on the growth and differentiation of keratinocytes were examined using cultured human keratinocytes (the squamous cell carcinoma cell line, DJM-1). The synthetic short-chain cell-permeant analogues of ceramides, N-acetylsphingosine, N-hexanoylsphingosine and N-octanoylsphingosine, significantly promoted differentiation as confirmed by upregulation of cornified envelope formation, synthesis of involucrin and increased transglutaminase activity, and inhibited proliferation as shown by a reduction in cell numbers, DNA amount and thymidine incorporation. Generally, these activities were greater the longer the N-acyl carbon chain. On the other hand, sphingosine at an appropriate concentration modestly stimulated the proliferation of cultured cells. Our results suggest the possibility that the growth and differentiation of keratinocytes are at least partially regulated by ceramide and sphingosine.