42 Polyprenol Could Prevent Loss of Filaggrin in Epithelial Cells in Atopic Dermatitis

BACKGROUND: In epithelial cells loss of filaggrin correlates with atopic dermatitis (AD) presence and activity. Dysregulation of DPAGT1 (Dolichyl-phosphate (UDP-N-acetylglucosamine) N-acetylglucosaminephosphotransferase 1 (GlcNAc-1-P transferase) causes disturbances in filaggrin expression. The resent results are in favour of the idea that N-glycosylation in keratinocytes cells is limited by Dolichyl Phosphate Cycle (DPC) intermediates. The aim of the present study is to investigate the effect of Polyprenol (PP), which provides a dolichol phosphate (DolP) substitute on regulation of filaggrin expression. METHODS: Filaggrin expression was measured in skin biopsies from 42 persons with AD and 36 with normal skin and cultured keratinocytes; PP concentration in the culture medium made up 10(−2) to 10(−6). Immunohistochemical and Western blotting methods were used to detect the changes in the expression levels of filaggrin and DPAGT1. IL-4 and IL-13 was determined using ELISA. Intermediates of DPC fractions were analysed by HPLC method. RESULTS: Overexpression of DPAGT1 was 5-fold higher in AD skin biopsies than in normal skin biopsies. AD cells differ from normal one in filaggrin content lost by 3 to 4 times. IL-4 and IL-13 cause overexpression and abberant N-glycosylation of filaggrin in DPC. The study showed overexpression of DPAGT1 and 6-fold DPC intermediates decrease in keratinocytes in presence of IL-13 and 2-fold in presence of IL-4 cells. Treatment of keratinocytes with PP resulted in downregulation of DPAGT1. It is established that PP in the concentration 10(−2) M could overcome DPAGT1 overexpression which leads to regulation of filaggrin N-glycosylation. CONCLUSIONS: IL-13 could cause DPAGT overexpression and dysregulation of N-glycosylation in keratinocytes which leads to AD fenotype affecting the stability of tight assembly and adherence junctions in skin. The findings indicate that DPAGT1 overexpression in keratinocytes treated with IL-4 and IL-13 can be overcomed by PP, which provides a DolP substitute for DPAGT1 normal expression, N-glycosylation and filaggrin loss prevention without neutralization of interleukins. Polyprenol could be a promising agent for atopic dermatis prevention and control.