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 cerami de, an important cell response modifier. Upon agonist-stimulation this path way is linked to biological responses as inhibition of proliferation, promo tion of differentiation and induction of apoptosis, One of the agonists des cribed is 1 alpha,25-dihydroxyvitamin D-3. Recently, we could demonstrate t he existence of sphingomyelin hydrolysis in human primary keratinocytes as well as in the human keratinocyte cell line HaCaT after treatment with 1 al pha,25-dihydroxyvitamin D-3, In the present study we tested four vitamin D analogues on HaCaT keratinocytes for their ability to inhibit cell prolifer ation and to induce sphingomyelin hydrolysis. These analogues, calcipotriol , EB 1213, GS 1500 and tacalcitol inhibit cell growth after 48 hrs. of incu bation 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, subsequent ly leading to the elevation of cellular ceramide levels, may represent an i mportant signal transduction pathway for 1 alpha,25-dihydroxyvitamin D-3 an d its analogues in human keratinocytes. Possible differences of the mechani sm underlying vitamin D-induced sphingomyelin hydrolysis has to be studied in more detail and may contribute to the antipsoriatic action of these anal ogues.