Topical Peroxisome Proliferator Activated Receptor-α Activators Reduce Inflammation in Irritant and Allergic Contact Dermatitis Models1 Mary Y. Sheu,

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Topical Peroxisome Proliferator Activated Receptor-α Activators Reduce Inflammation in Irritant and Allergic Contact Dermatitis Models1 Mary Y. Sheu, Ashley J. Fowler, Jack Kao, Matthias Schmuth, Joachim W. Fluhr, Mao-Qiang Man, Peter M. Elias, Kenneth R. Feingold Journal of Investigative Dermatology Volume 118, Issue 1, Pages 94-101 (January 2002) DOI: 10.1046/j.0022-202x.2001.01626.x Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 PPAR-α activators reduce TPA-induced ear swelling. Ear thickness (A) and ear weight (B) are markedly increased in TPA-induced irritant dermatitis. Topical treatment with clobetasol, or the PPAR-α activators clofibrate, WY 14643, and linoleic acid 45 min and 4 h following TPA treatment reduce the increase in ear thickness and ear weight, whereas stearic acid, a free fatty acid that does not activate PPAR-α has no effect. Data are presented as mean ± SEM; n = 4–8; *p < 0.05. Statistical significance was determined using ANOVA. Journal of Investigative Dermatology 2002 118, 94-101DOI: (10.1046/j.0022-202x.2001.01626.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Dose–response curves. Dose–responses show that the increase in ear thickness (A, C) and weight (B, D) induced by TPA is inhibited similarly by clobetasol and WY 14643. Data are presented as mean ± SEM. n = 5 for each group. Journal of Investigative Dermatology 2002 118, 94-101DOI: (10.1046/j.0022-202x.2001.01626.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Clofibrate does not alter TPA-induced ear swelling in PPAR-α–/– mice. Topical application of clofibrate does not reduce the TPA-induced ear swelling response in PPAR-α–/– mice (n = 3). In wild-type animals (C57BL/6 and SV1) (n = 4) clofibrate treatment leads to a marked reduction in ear thickness comparable with that observed in CD-1 mice. Data are presented as mean ± SEM; *p < 0.05. Statistical significance was determined using a Student's two-tailed T-test. Journal of Investigative Dermatology 2002 118, 94-101DOI: (10.1046/j.0022-202x.2001.01626.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 PPAR-α activators reduce the TPA-induced increase in ear thickness and inflammation. H&E-stained sections of normal mouse ear (A), TPA-induced irritant dermatitis (B), clobetasol treated (C), and clofibrate treated (D). TPA treatment results in a marked increase in ear thickness and a prominent mononuclear cell infiltrate in the dermis (B). Clofibrate treatment reduces ear thickness and the number of inflammatory cells to an extent comparable with clobetasol (C vs D). Sections shown are representative of observations from three animals in each group. Journal of Investigative Dermatology 2002 118, 94-101DOI: (10.1046/j.0022-202x.2001.01626.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 PPAR-α activators reduce oxazalone-induced ear swelling. Ear thickness (A) and ear weight (B) are markedly increased in oxazolone-induced allergic contact dermatitis. Clofibrate (1 mM) treatment reduces oxazalone-induced ear thickness (A) and weight (B), whereas clobetasol (0.05%) treatment almost entirely eliminates oxazalone-induced inflammation. Data are presented as mean ± SEM; n = 7; *p < 0.05. Statistical significance was determined using ANOVA. Journal of Investigative Dermatology 2002 118, 94-101DOI: (10.1046/j.0022-202x.2001.01626.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 PPAR-α activators ameliorate oxazolone-induced inflammatory infiltrates. H&E-stained sections of normal mouse ear (A), oxazalone-induced allergic contact dermatitis (B), clobetasol treated (C), and clofibrate treated (D). Oxazolone induces a marked increase in ear thickness and a mononuclear cell infiltrate in the dermis. Clobetasol or clofibrate treatment reduces ear thickness and decreases the number of inflammatory cells. Sections shown are representative of observations from three animals in each group. Journal of Investigative Dermatology 2002 118, 94-101DOI: (10.1046/j.0022-202x.2001.01626.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 7 PPAR-α activators reduce IL-1α and TNF-α expression in TPA-induced irritant dermatitis. Immunohistochemical staining reveals an increase in IL-1α and TNF-α expression in the epidermis and dermis after TPA treatment. Topical clofibrate treatment reduces IL-1α and TNF-α staining comparable with clobetasol. Sections shown are representative of observations from three animals in each group. Scale bars: 10 µm. Journal of Investigative Dermatology 2002 118, 94-101DOI: (10.1046/j.0022-202x.2001.01626.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 8 PPAR-α activators reduce oxazalone-induced IL-1α and TNF-α expression. Immunohistochemical staining of IL-1α and TNF-α in oxazalone-induced allergic contact dermatitis treated with acetone vehicle, clobetasol treated, and clofibrate treated. Oxazolone treatment results in an increase in epidermal and dermal IL-1α and TNF-α staining. With clobetasol and clofibrate treatment IL-1α and TNF-α staining is reduced. Sections shown are representative of observations from three animals in each group. Scale bars: 10 µm. Journal of Investigative Dermatology 2002 118, 94-101DOI: (10.1046/j.0022-202x.2001.01626.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions