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

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.