1,25-Dihydroxyvitamin D3 inhibits ultraviolet B-induced apoptosis, Jun kinase activation, and interleukin-6 production in primary human keratinocytes.
We investigated the capacity of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] to protect human keratinocytes against the hazardous effects of ultraviolet B (UVB)-irradiation, recognized as the most important etiological factor in the development of skin cancer. Cytoprotective effects of 1,25(OH)(2)D(3) on UVB-irradiated keratinocytes were seen morphologically and quantified using a colorimetric survival assay. Moreover, 1,25(OH)(2)D(3) suppressed UVB-induced apoptotic cell death. An ELISA, detecting DNA-fragmentation, demonstrated that pretreatment of keratinocytes with 1,25(OH)(2)D(3) 1 microM for 24 h reduced UVB-stimulated apoptosis by 55-70%. This suppression required pharmacological concentrations 1,25(OH)(2)D(3) and a preincubation period of several hours. In addition, 1,25(OH)(2)D(3) also inhibited mitochondrial cytochrome c release (90%), a hallmark event of UVB-induced apoptosis. Furthermore, we demonstrated that 1,25(OH)(2)D(3) reduced two important mediators of the UV-response, namely, c-Jun-NH(2)-terminal kinase (JNK) activation and interleukin-6 (IL-6) production. As shown by Western blotting, pretreatment of keratinocytes with 1,25(OH)(2)D(3) 1 microM diminished UVB-stimulated JNK activation with more than 30%. 1,25(OH)(2)D(3) treatment (1 microM) reduced UVB-induced IL-6 mRNA expression and secretion with 75-90%. Taken together, these findings suggest the existence of a photoprotective effect of active vitamin D(3) and create new perspectives for the pharmacological use of active vitamin D compounds in the prevention of UVB-induced skin damage and carcinogenesis.
De Haes
Petra
P
Laboratory for Experimental Medicine and Endocrinology (LEGENDO), Gasthuisberg, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Garmyn
Marjan
M
Degreef
Hugo
H
Vantieghem
Katleen
K
Bouillon
Roger
R
Segaert
Siegfried
S
D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D015152:Blotting, Northern; D015153:Blotting, Western; D002117:Calcitriol / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D045304:Cytochromes c / Q000096:biosynthesis / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000528:radiation effects; D048031:JNK Mitogen-Activated Protein Kinases; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects*; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000528:radiation effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000528:radiation effects; D014466:Ultraviolet Rays; D015854:Up-Regulation / Q000528:radiation effects
D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D045304:Cytochromes c; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D002117:Calcitriol