Topical peroxisome proliferator activated receptor-alpha activators reduce inflammation in irritant and allergic contact dermatitis models.
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.
Sheu
Mary Y
MY
Department of Medicine, University of California San Francisco School of Medicine, San Francisco, California, USA.
Fowler
Ashley J
AJ
Kao
Jack
J
Schmuth
Matthias
M
Schoonjans
Kristina
K
Auwerx
Johan
J
Fluhr
Joachim W
JW
Man
Mao-Qiang
MQ
Elias
Peter M
PM
Feingold
Kenneth R
KR
D000276:Adjuvants, Immunologic; D000287:Administration, Topical; D000818:Animals; D002994:Clofibrate / Q000494:pharmacology; D017449:Dermatitis, Allergic Contact / Q000276:immunology / Q000473:pathology*; D003875:Drug Eruptions / Q000473:pathology*; D005260:Female; D007375:Interleukin-1 / Q000037:antagonists & inhibitors; D007509:Irritants; D019787:Linoleic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout / Q000235:genetics; D010081:Oxazolone / Q000276:immunology; D011743:Pyrimidines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate; D014157:Transcription Factors / Q000819:agonists* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D000276:Adjuvants, Immunologic; D007375:Interleukin-1; D007509:Irritants; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D010081:Oxazolone; C006253:pirinixic acid; D019787:Linoleic Acid; D002994:Clofibrate; D013755:Tetradecanoylphorbol Acetate