Activators of peroxisome proliferator-activated receptors protect human skin from ultraviolet-B-light-induced inflammation

J Invest Dermatol. 2001 Dec;117(6):1430-6. doi: 10.1046/j.0022-202x.2001.01537.x.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Division / drug effects
  • Cell Line, Transformed
  • DNA Primers
  • Dermatitis / metabolism*
  • Down-Regulation / radiation effects
  • Erythema / metabolism
  • Gene Expression / immunology
  • Gene Expression / radiation effects
  • Humans
  • Interleukin-6 / genetics
  • Interleukin-8 / genetics
  • Keratinocytes / cytology
  • Keratinocytes / metabolism
  • Keratinocytes / radiation effects
  • Peroxisome Proliferators / pharmacology
  • Pyrimidines / pharmacology
  • Receptors, Cytoplasmic and Nuclear / genetics*
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Response Elements / physiology
  • Skin / cytology
  • Skin / immunology
  • Skin / radiation effects*
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*
  • Ultraviolet Rays / adverse effects

Substances

  • DNA Primers
  • Interleukin-6
  • Interleukin-8
  • Peroxisome Proliferators
  • Pyrimidines
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • pirinixic acid