Topical peroxisome proliferator activated receptor-alpha activators reduce inflammation in irritant and allergic contact dermatitis models
| Autor: | Ashley J. Fowler, Jack Kao, Kristina Schoonjans, Kenneth R. Feingold, Mary Y. Sheu, Joachim W. Fluhr, Matthias Schmuth, Johan Auwerx, Peter M. Elias, Mao-Qiang Man |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Male
Peroxisome proliferator-activated receptor gamma medicine.medical_specialty Administration Topical Receptors Cytoplasmic and Nuclear Inflammation Mice Inbred Strains Dermatology Retinoid X receptor Biology Biochemistry Linoleic Acid 030207 dermatology & venereal diseases 03 medical and health sciences Mice 0302 clinical medicine Adjuvants Immunologic Internal medicine medicine Animals Clofibrate Receptor Molecular Biology Allergic contact dermatitis 030304 developmental biology Mice Knockout 0303 health sciences Tumor Necrosis Factor-alpha Oxazolone Cell Biology medicine.disease 3. Good health Endocrinology Pyrimidines Dermatitis Allergic Contact Irritants Tetradecanoylphorbol Acetate Tumor necrosis factor alpha Female Peroxisome proliferator-activated receptor alpha Drug Eruptions medicine.symptom medicine.drug Interleukin-1 Transcription Factors |
| Zdroj: | The Journal of investigative dermatology. 118(1) |
| ISSN: | 0022-202X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|