Different vitamin D analogues induce sphingomyelin hydrolysis and apoptosis in the human keratinocyte cell line HaCaT.

Sphingomyelin hydrolysis seems to be a ubiquitous pathway generating ceramide, an important cell response modifier. Upon agonist-stimulation this pathway is linked to biological responses as inhibition of proliferation, promotion of differentiation and induction of apoptosis. One of the agonists described is 1alpha,25-dihydroxyvitamin D3. Recently, we could demonstrate the existence of sphingomyelin hydrolysis in human primary keratinocytes as well as in the human keratinocyte cell line HaCaT after treatment with 1alpha,25-dihydroxyvitamin D3. In the present study we tested four vitamin D analogues on HaCaT keratinocytes for their ability to inhibit cell proliferation and to induce sphingomyelin hydrolysis. These analogues, calcipotriol, EB 1213, GS 1500 and tacalcitol inhibit cell growth after 48 hrs. of incubation and trigger the hydrolysis of sphingomyelin. Moreover, all analogues tested induce apoptotic cell death in HaCaT keratinocytes after 24 hrs. of incubation. This study indicates that sphingomyelin hydrolysis, subsequently leading to the elevation of cellular ceramide levels, may represent an important signal transduction pathway for 1alpha,25-dihydroxyvitamin D3 and its analogues in human keratinocytes. Possible differences of the mechanism underlying vitamin D-induced sphingomyelin hydrolysis has to be studied in more detail and may contribute to the antipsoriatic action of these analogues.