Topical peroxisome proliferator activated receptor-alpha activators reduce inflammation in irritant and allergic contact dermatitis models

J Invest Dermatol. 2002 Jan;118(1):94-101. doi: 10.1046/j.0022-202x.2001.01626.x.


Activators of peroxisome proliferator activated receptor-alpha, 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-alpha 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-alpha 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-alpha 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-alpha, 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-alpha-/- mice, indicating that the anti-inflammatory effect is mediated by peroxisome proliferator activated receptor-alpha. As tumor necrosis factor-alpha and interleukin-1alpha are major mediators of cutaneous inflammation we next used immunohistochemistry to determine whether the peroxisome proliferator activated receptor-alpha 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-1alpha 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-alpha and interleukin-1alpha levels in the oxazalone-treated epidermis. These studies demonstrate that topically applied peroxisome proliferator activated receptor-alpha 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-alpha 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adjuvants, Immunologic
  • Administration, Topical
  • Animals
  • Clofibrate / pharmacology
  • Dermatitis, Allergic Contact / immunology
  • Dermatitis, Allergic Contact / pathology*
  • Drug Eruptions / pathology*
  • Female
  • Interleukin-1 / antagonists & inhibitors
  • Irritants*
  • Linoleic Acid / pharmacology
  • Male
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout / genetics
  • Oxazolone / immunology
  • Pyrimidines / pharmacology
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Tetradecanoylphorbol Acetate
  • Transcription Factors / agonists*
  • Transcription Factors / genetics
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors


  • Adjuvants, Immunologic
  • Interleukin-1
  • Irritants
  • Pyrimidines
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • Oxazolone
  • pirinixic acid
  • Linoleic Acid
  • Clofibrate
  • Tetradecanoylphorbol Acetate