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01.10.2004 | Original Paper | Ausgabe 5/2004

Archives of Dermatological Research 5/2004

1α,25(OH)2D3 regulates NF-κB DNA binding activity in cultured normal human keratinocytes through an increase in IκBα expression

Zeitschrift:
Archives of Dermatological Research > Ausgabe 5/2004
Autoren:
Jette L. Riis, Claus Johansen, Borbala Gesser, Kristine Møller, Christian G. Larsen, Knud Kragballe, Lars Iversen

Abstract

NF-κB is a dimeric transcription factor which regulates transcription of a number of different genes including IL-8 and p53. In resting cells NF-κB is usually retained in an inactive state in the cytoplasm through binding to a member of the inhibitory κB (IκB) protein family. The purpose of this study was to determine the effect of 1α,25(OH)2D3 on NF-κB activation in both unstimulated and stimulated (IL-1α) cultured normal human keratinocytes. NF-κB DNA binding activity was determined by EMSA using two different oligonucleotides containing the κB sequence from either the IL-8 or the p53 promoter. IκBα and p53 expression was determined by Western blotting and IL-8 expression by ELISA. In unstimulated keratinocytes no NF-κB binding to the IL-8 κB binding sequence was detectable, whereas stimulation with IL-1α (10 ng/ml) led to a significant (P<0.05) induction of NF-κB binding. In contrast NF-κB binding to the p53 κB binding sequence was detectable in unstimulated cells, although it was significantly increased after IL-1α (10 ng/ml) stimulation. Incubation with 1α,25(OH)2D3 (10−8–10−7 M) was shown to significantly (P<0.05) stimulate the expression of IκBα and in parallel experiments with normal human keratinocytes stimulated with IL-1α (10 ng/ml) a significant (P<0.05) time and dose-dependent decrease in NF-κB binding to the IL-8 κB binding sequence and in IL-8 expression were seen. A less-pronounced decrease in NF-κB binding to the p53 κB response element was seen after preincubation with 1α,25(OH)2D3 and IL-1α stimulation, and it did not result in any change in p53 expression. These results demonstrate that 1α,25(OH)2D3 inhibits NF-κB binding to the IL-8 κB binding sequence more potently than binding to the p53 κB binding sequence. We propose that this selectivity may be mediated through an increased expression of IκBα which leads to an inhibition of specific NF-κB subunits resulting in a selective regulation of NF-κB-induced gene transcription.

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