Synergy Between Vitamin D Precursor 25-hydroxyvitamin D and Short Chain Ceramides on Keratinocyte Proliferation and Differentiation

The active vitamin D metabolite, 1,25-dihydroxyvitamin D3 (1,25D), and its analogs induce normal human keratinocyte differentiation and are used for the treatment of psoriasis. Long-term topical use of 1,25D, however, causes hypercalcemia. The precursor of 1,25D, 25-hydroxyvitamin D3 (25D) is converted to 1,25D in the keratinocyte in a regulated manner. The action of 1,25D is reported to be mediated, at least in part, by cellular ceramides in the leukemia cell line, HL-60 cells. Therefore, in this study we evaluated the synergy between 25D and short chain cell permeable ceramides (SCC) or synthetic analogs of ceramides on keratinocyte growth and differentiation in vitro. C2 ceramide (acetyl sphingosine) synergistically enhanced the growth inhibitory effect of 25D and 1,25D in a concentration-dependent manner. Short chain analogs of ceramide-like compounds, neoceramides and pseudoceramides, also inhibited keratinocyte proliferation and acted in synergy with 25D and 1,25D. SCC alone increased transglutaminase and cornified envelope levels. 25D potentiated this prodifferentiating effect of SCC. Twenty-four-hour preincubation with SCC did not alter 25D or 1,25D uptake into keratinocytes. These studies demonstrate a synergy between vitamin D metabolites and ceramides in human keratinocytes and indicate the potential of using 25D as an effective and safer alternative to deliver 1,25D benefits to the epidermis.