1. ¹Department of Medicine and Dermatology, University of California San Francisco School of Medicine, San Francisco, California and the Dermatology and Medical Services, Department of Veteran Affairs Medical Center, San Francisco, California, U.S.A.
2. ^*Institut de Génetique et Biologie Cellulaire et Moléculaire (IGBMC), CNRS/INSERM/Université Louis Pasteur, Illkirch, France

Correspondence: Dr Kenneth R. Feingold, Metabolism Section (111F), Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121. Email: kfngld@itsa.ucsf.edu

²Both of these authors contributed equally to this manuscript.

¹The authors declared no conflict of interest.

Received 28 March 2001; Revised 21 September 2001; Accepted 8 October 2001.

Abstract

Activators of peroxisome proliferator activated receptor-, 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- 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- 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- 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-, 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-^–/– mice, indicating that the anti-inflammatory effect is mediated by peroxisome proliferator activated receptor-. As tumor necrosis factor- and interleukin-1 are major mediators of cutaneous inflammation we next used immunohistochemistry to determine whether the peroxisome proliferator activated receptor- agonists reduce the levels of these cytokines in 12-O-tetradecanoylphorbol-13-acetate-treated skin. 12-O-tetradecanoylphorbol-13-acetate treatment resulted in an increase in tumor necrosis factor and interleukin-1 staining in the epidermis that was reduced by clofibrate treatment. Finally, clofibrate treatment also reduced ear thickness and weight in oxazalone-induced allergic dermatitis, a change that was accompanied by a reduction in inflammatory cells in the dermis and a decrease in tumor necrosis factor- and interleukin-1 levels in the oxazalone-treated epidermis. These studies demonstrate that topically applied peroxisome proliferator activated receptor- agonists possess receptor mediated, anti-inflammatory activity in both irritant and allergic contact dermatitis animal models. The anti-inflammatory properties of peroxisome proliferator activated receptor- agonists, coupled with their anti-proliferative and pro-differentiating effects, suggest that they could be beneficial for the treatment of a variety of cutaneous diseases.