Nicotinamide increases biosynthesis of ceramides as well as other stratum corneum lipids to improve the epidermal permeability barrier.

BACKGROUND: Stratum corneum lipids, particularly ceramides, are important components of the epidermal permeability barrier that are decreased in atopic dermatitis and aged skin. OBJECTIVES: We investigated the effects of nicotinamide, one of the B vitamins, on biosynthesis of sphingolipids, including ceramides and other stratum corneum lipids, in cultured normal human keratinocytes, and on the epidermal permeability barrier in vivo. METHODS: The rate of sphingolipid biosynthesis was measured by the incorporation of [14C]-serine into sphingolipids. RESULTS: When the cells were incubated with 1-30 micromol L-1 nicotinamide for 6 days, the rate of ceramide biosynthesis was increased dose-dependently by 4.1-5. 5-fold on the sixth day compared with control. Nicotinamide also increased the synthesis of glucosylceramide (7.4-fold) and sphingomyelin (3.1-fold) in the same concentration range effective for ceramide synthesis. Furthermore, the activity of serine palmitoyltransferase (SPT), the rate-limiting enzyme in sphingolipid synthesis, was increased in nicotinamide-treated cells. Nicotinamide increased the levels of human LCB1 and LCB2 mRNA, both of which encode subunits of SPT. This suggested that the increase in SPT activity was due to an increase in SPT mRNA. Nicotinamide increased not only ceramide synthesis but also free fatty acid (2.3-fold) and cholesterol synthesis (1.5-fold). Topical application of nicotinamide increased ceramide and free fatty acid levels in the stratum corneum, and decreased transepidermal water loss in dry skin. CONCLUSIONS: Nicotinamide improved the permeability barrier by stimulating de novo synthesis of ceramides, with upregulation of SPT and other intercellular lipids.

UVB-induced alterations in permeability barrier function: roles for epidermal hyperproliferation and thymocyte-mediated response.

UV irradiation induces a variety of cutaneous responses, including disruption of epidermal permeability barrier function, the basis for which is not known. Herein, we investigated the separate roles of hyperproliferation and inflammation in the pathogenesis of UVB-induced barrier disruption. Adult hairless mice were exposed to increasing doses of UVB (1.5-7.5 MED), and transepidermal water loss (TEWL) was monitored daily for up to 7 d. The extent of TEWL increase was dependent on the UVB dose, but with all doses, the increase began after > or =48 h and peaked at 96 h, decreasing by 120 h. Epidermal [(3)H]thymidine incorporation increased at 24 h and peaked at 48 h (570%), preceding the maximal increase in TEWL. Cyclosporin A, methotrexate, 5-fluorouracil, or arabinosylcytosine significantly diminished the UVB-induced TEWL increase. Athymic nude mice also displayed a markedly diminished response to UVB, and DNA synthesis did not increased at 48 h. Transplantation of athymic mice with T-cell-enriched mixed immune cells significantly restored sensitivity to both the UVB-induced hyperproliferation and the barrier defect. Finally, although UVB exposure increased PGE2 levels in whole skin samples (2- to 3-fold within 1-3 h; p < 0.005), this increase was completely blocked by topical indomethacin, and neither topical indomethacin nor topical glucocorticoids blocked development of the barrier abnormality. These results show that (i) UVB produces delayed alteration in barrier function and (ii) both an epidermal proliferative response and thymocyte-mediated events (but not PGE2 production and nonspecific inflammation) appear to contribute to UVB-induced abrogation of the permeability barrier.

Effects of ethyl alpha-D-glucoside on skin barrier disruption.

Daily treatments of skin in hairless mice with concentrates of rice wine, Japanese traditional alcohol, lowered transepidermal water loss levels compared to the controls on the 3rd day after ultraviolet B (UVB) irradiation. These findings indicate that the concentrates of rice wine suppress the murine skin barrier disruption caused by UVB. Ethyl alpha-D-glucoside (alpha-ethylglucoside), one of the peculiar components in rice wine, showed the same effect, whereas beta-ethylglucoside had no effect. In order to clarify the functions of alpha-ethylglucoside on murine skin, we examined the effects of this compound on the expression of some phenotypes in human keratinocytes in vitro. As a result, alpha-ethylglucoside as well as beta-ethylglucoside enhanced cell proliferation weakly, and the formation of cornified envelopes and differentiated type keratin (K1) in keratinocytes was accelerated by alpha-ethylglucoside but not by beta-ethylglucoside. From the results, we conclude that alpha-ethylglucoside enhanced the differentiation of keratinocytes, which might be related to reduced barrier disruption by UVB.