linoleic-acid and Dermatitis--Allergic-Contact

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 demonstra

Topics: Adjuvants, Immunologic; Administration, Topical; Animals; Clofibrate; Dermatitis, Allergic Contact; Drug Eruptions; Female; Interleukin-1; Irritants; Linoleic Acid; Male; Mice; Mice, Inbred Strains; Mice, Knockout; Oxazolone; Pyrimidines; Receptors, Cytoplasmic and Nuclear; Tetradecanoylphorbol Acetate; Transcription Factors; Tumor Necrosis Factor-alpha

Topics: Adult; Aged; Alkanes; Biopsy; Child; Cosmetics; Dermatitis, Allergic Contact; Dermatitis, Contact; Dermatitis, Irritant; Dermatitis, Phototoxic; Diagnosis, Differential; Disease Outbreaks; Female; Haptens; Humans; Linoleic Acid; Linoleic Acids; Male; Middle Aged; Patch Tests; Product Surveillance, Postmarketing; Pruritus; Skin; Sunlight; Switzerland; Urticaria; Vitamin E