Activators of peroxisome proliferator-activated receptors protect human skin from ultraviolet-B-light-induced inflammation.
Peroxisome proliferator-activated receptors (PPAR) are members of a nuclear receptor superfamily, which were initially described in the context of fatty acid degradation and adipocyte differentiation. In this study we tested the hypothesis that peroxisome proliferator-activated receptor activation also controls inflammation. In an in vitro model with human keratinocytes inflammation was mimicked by irradiation with ultraviolet B light (150 mJ per cm(2)). Activators for PPAR-alpha (WY-14,643, clofibrate) were shown to reverse ultraviolet-B-light-mediated expression of inflammatory cytokines (interleukin-6, interleukin-8). An activator preferentially for PPAR-beta (bezafibrate) did not show prominent effects on interleukin-6 and interleukin-8 expression. The anti-inflammatory action of WY-14,643 on skin cells was further demonstrated by in vivo testings in which topically applied WY-14,643 markedly increased the minimal erythema dose in ultraviolet-B-irradiated skin. Additionally, it was shown that ultraviolet B irradiation led to a decrease of all three peroxisome proliferator-activated receptor subsets at the mRNA level. Also transactivation of peroxisome proliferator response element was attenuated by ultraviolet B irradiation. The downregulation of peroxisome proliferator-activated receptors by ultraviolet B irradiation provides a possible mechanism that leads to exaggerated and prolonged inflammation. This work suggests the possibility of PPAR-alpha activators as novel nonsteroidal anti-inflammatory drugs in the topical treatment of common inflammatory skin diseases such as atopic dermatitis, psoriasis, and photodermatitis.
Kippenberger
S
S
Department of Dermatology and Venerology, Klinikum der Johann Wolfgang Goethe Universitaet, Frankfurt/Main, Germany. kippenberger@em.uni-frankfurt.de
Loitsch
S M
SM
Grundmann-Kollmann
M
M
Simon
S
S
Dang
T A
TA
Hardt-Weinelt
K
K
Kaufmann
R
R
Bernd
A
A
D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D017931:DNA Primers; D003872:Dermatitis / Q000378:metabolism*; D015536:Down-Regulation / Q000528:radiation effects; D004890:Erythema / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology / Q000528:radiation effects; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D020025:Peroxisome Proliferators / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism*; D020218:Response Elements / Q000502:physiology; D012867:Skin / Q000166:cytology / Q000276:immunology / Q000528:radiation effects*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014466:Ultraviolet Rays / Q000009:adverse effects
D017931:DNA Primers; D015850:Interleukin-6; D016209:Interleukin-8; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C006253:pirinixic acid