Topical Peroxisome Proliferator Activated Receptor-α Activators Reduce Inflammation in Irritant and Allergic Contact Dermatitis Models1.

Activators of peroxisome proliferator activated receptor-α, a nuclear hormone receptor that heterodimerizes with retinoid X receptor, stimulate epidermal differentiation and inhibit proliferation. Here we determined the anti-inflammatory effects of peroxisome proliferator activated receptor-α agonists in models of irritant and allergic contact dermatitis produced in mouse ears by topical treatment with 12-O-tetradecanoylphorbol-13-acetate and oxazalone, respectively. As expected, 12-O-tetradecanoylphorbol-13-acetate treatment resulted in a marked increase in the thickness and weight of the ears and provoked an inflammatory cell infiltrate in the dermis. Topical treatment with three different peroxisome proliferator activated receptor-α agonists, clofibrate, WY 14643, or linoleic acid, 45 min and 4 h after 12-O-tetradecanoylphorbol-13-acetate application, resulted in a marked decrease in ear thickness and weight and a reduction in the number of inflammatory cells in the dermis. The reduction in inflammation by these peroxisome proliferator activated receptor-α agonists was of similar magnitude to that seen with a potent topical glucocorticoid, clobetasol. In contrast, stearic acid, a free fatty acid that does not activate peroxisome proliferator activated receptor-α, had no effect on the 12-O-tetradecanoylphorbol-13-acetate-induced inflammation. Moreover, clofibrate did not significantly alter ear thickness following 12-O-tetradecanoylphorbol-13-acetate treatment in peroxisome proliferator activated receptor-α–/– mice, indicating that the anti-inflammatory effect is mediated by peroxisome proliferator activated receptor-α. As tumor necrosis factor-α and interleukin-1α are major mediators of cutaneous inflammation we next used immunohistochemistry to determine whether the peroxisome proliferator activated receptor-α agonists reduce the levels of these cytokines in... [ABSTRACT FROM AUTHOR]