EFFECTS OF 1,25-DIHYDROXYVITAMIN-D-3 AND ITS 20-EPI ANALOGS (MC-1288,MC-1301, KH-1060), ON CLONAL KERATINOCYTE GROWTH - EVIDENCE FOR DIFFERENTIATION OF KERATINOCYTE STEM-CELLS AND ANALYSIS OF THE MODULATORY EFFECTS OF CYTOKINES

1. Keratinocytes are functionally divided into stem cells, transit amp lifying cells and terminally differentiated cells. In a hyperprolifera tive skin disease, psoriasis, increased mitotic activity of the stem c ells is chiefly responsible for epidermal hyperplasia. The effects of 1,25dihydroxyvitamin D-3 (1,25(OH)(2)D-3 and potent vitamin D-3 analog ues (MC 1288: 20-epi-1,25(OH)(2)D-3, MC 1301: 20-epi-24a-homo-26,27-di methyl-1,25(OH)(2)D-3, KH 1060: epi-22-oxa-24a-homo-26,27-dimethyl-1,2 5(OH)(2)D-3) on the stem cells were investigated. 2 Stem cells were id entified retrospectively as those giving rise to large keratinocyte co lonies in culture (holoclones). 1,25(OH)(2)D-3 (10(-8)-10(-6) M) suppr essed formation of holoclones by stimulating the progenitor cell diffe rentiation into the phenotype expressing differentiation markers (kera tins K1/K10 and involucrin). 3 20-Epi vitamin D-3 analogues were mon p otent than 1,25(OH)(2)D-3 in inhibiting the clonal keratinocyte growth . This activity correlated with the ability to induce cell differentia tion (KH 1060>MC 1301>MC 1288>1,25(OH)(2)D-3). 4 Cytokines modulated t he effects of 1,25(OH)(2)D-3 on clonal growth. One of the following cy tokines (epidermal growth factor, transforming growth factor alpha, in terleukin-1 alpha, interleukin-1 beta, interleukin-6, interleukin-8) w as required for 1,25(OH)(2)D-3 to suppress clonal growth and induce ce ll differentiation. In contrast, keratinocyte growth factor and insuli n-like growth factor I attenuated the effects of 1,25(OH)(2)D-3. 5 In conclusion, 1,25(OH)(2)D-3 and 20-epi vitamin D-3 analogues suppress c lonal growth by directly inducing the differentiation of progenitor ce lls. It is conceivable that stimulation of stem cells differentiation is a major mechanism of action of vitamin D-3 compounds in psoriasis. Balance between different types of cytokines in psoriatic epidermis ma y be an important factor determining the clinical effect of vitamin D- based therapy.