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Inverse Regulation of the Nuclear Factor-κB Binding to the p53 and Interleukin-8 κB Response Elements in Lesional Psoriatic Skin
Ist Teil von
Journal of investigative dermatology, 2005-06, Vol.124 (6), p.1284-1292
Ort / Verlag
London: Elsevier Inc
Erscheinungsjahr
2005
Link zum Volltext
Quelle
Alma/SFX Local Collection
Beschreibungen/Notizen
Nuclear factor-κB (NF-κB) is an inducible nuclear transcription factor regulating a range of cellular processes. An imbalance of the DNA binding activity of NF-κB may, therefore, be part of the pathophysiological mechanisms in psoriasis. The purpose of this study was to determine the NF-κB DNA binding activity in psoriatic skin using three different κB sites and to determine how DNA binding activity was modulated by the anti-psoriatic drug calcipotriol. By electrophoretic mobility shift assay, we demonstrated that the NF-κB DNA binding to the p53 κB site was decreased, whereas the NF-κB DNA binding to the interleukin-8 (IL-8) κB site was increased in lesional psoriatic skin compared with non-lesional psoriatic skin. No regulation was seen on the NF-κB DNA binding to the major histocompatibility complex class I κB site. These changes were paralleled by a similar decrease in p53 expression and an increase in IL-8 expression in involved psoriatic skin compared with uninvolved skin as determined by quantitative RT-PCR. The alteration in NF-κB DNA binding activity was neither accompanied by any change in the expression of the inhibitor κB (IκB) kinases, IKKα, IKKβ, and IKKγ nor in the expression of the NF-κB inhibitor proteins, IκBα and IκBβ. Immunofluorescence analysis revealed that p65 was sequestered in the cytoplasm of keratinocytes, whereas p50 exhibited a cytoplasmic as well as a nuclear localization. Interestingly, this distribution of p50 and p65 was similar in lesional and non-lesional psoriatic skin. Topical application of calcipotriol to lesional psoriatic skin for 4 d resulted in increased NF-κB binding to the p53 κB site and decreased NF-κB binding to the IL-8 κB site. Taken together, our data demonstrate that the NF-κB DNA binding activity is regulated in a specific manner in psoriatic skin depending on the κB sites investigated, and that topical treatment of psoriatic skin normalizes the abnormal NF-κB binding activity seen in lesional psoriatic skin.