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

Abstract

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.

Physical and Chemical Factors that Improve Epidermal Permeability Barrier Homeostasis

“…Cornified envelope formation and involucrin and transglutaminase protein and mRNA levels were also increased by the activation of PPAR (Feingold 2000). Interestingly, the inflammatory response was also inhibited (Sheu 2002). Topical application of PPAR activators accelerated barrier recovery after tape stripping or acetone treatment and prevented the epidermal hyperplasia induced by repeated barrier disruption (Feingold 1999).…”

Peroxisome Proliferator-Activated Receptor-α Activation Inhibits Langerhans Cell Function

“…In a mouse model of allergic contact dermatitis, topical treatment with PPAR␣ agonists was reported to ameliorate ear swelling, which correlated with a reduction in the magnitude of the lymphocytic infiltrate and a decreased expression of proinflammatory cytokines (14). In PPAR␣ knockout animals, it was demonstrated that these effects were receptor mediated (14). However, the mechanisms by which PPAR␣ activation exerts its antiinflammatory effects in allergic contact dermatitis are not known.…”

“…Thus, one may speculate that PPAR␣ activation inhibits the production of IL-1␤ in the epidermis, resulting in the decrease of migratory capacity of LC and in their production of TNF-␣. Ultimately, this may result in a decreased adaptive immune response (14).…”

Thematic Review Series: Skin Lipids. Peroxisome proliferator-activated receptors and liver X receptors in epidermal biology

“…A mouse model measures ear swelling in mice after topically applying 12-O-tetradecanoylphorbol-13-acetate (TPA) to the ears, a model of irritant contact dermatitis; a second model measures ear swelling after topical application of an allergen (e.g., oxazolone), first to the abdomen and then several days later to the ears, a model of allergic contact dermatitis. In these models, simultaneous topical treatment with PPARa agonists reduced ear swelling, the magnitude of the inflammatory infiltrate, and the expression of tumor necrosis factor-a (TNF-a) and interleukin-1a (IL-1a) (46,47). Moreover, PPARa activation inhibited cytokine secretion, maturation, and migration and the T-cell-stimulatory activity of the epidermal antigen-presenting cell, the Langerhans cell.…”