Transgenic Expression of Interleukin-13 in the Skin Induces a Pruritic Dermatitis and Skin Remodeling Tao Zheng, Min H. Oh, Sun Y. Oh, John T. Schroeder,

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Transgenic Expression of Interleukin-13 in the Skin Induces a Pruritic Dermatitis and Skin Remodeling Tao Zheng, Min H. Oh, Sun Y. Oh, John T. Schroeder, Adam B. Glick, Zhou Zhu Journal of Investigative Dermatology Volume 129, Issue 3, Pages 742-751 (March 2009) DOI: 10.1038/jid.2008.295 Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Targeting IL-13 to the skin. (a) Schematic construct of TRE-Tight-IL-13. (b) Tissue specificity of IL-13 expression in Tg(+) mice as determined by RT–PCR. The experiments were started by withdrawing Dox and total RNA from different tissues was analyzed for IL-13 mRNA expression. (c) IL-13 mRNA expression in the skin of Tg(+) mice in comparison with Tg(-) mice 6 weeks off Dox. (d) IL-13 protein in the skin extract 8 weeks after Dox withdrawal (n=36, each group). Journal of Investigative Dermatology 2009 129, 742-751DOI: (10.1038/jid.2008.295) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 IL-13-induced AD. (a) Gross comparison of a Tg(+) mouse and a Tg(-) mouse off Dox for 8 weeks. Tg(+) mice developed inflammatory skin lesions in the back and abdomen areas with hair loss, dry skin, excoriation, crusting, and bacterial pyoderma. Clinical scores of dermatitis in a representative group of Tg(+) mice (n=7) after induction of IL-13 transgene for varying time. Tg(-) mice and Tg(+) mice without induction did not show any clinical signs of dermatitis. (b) Skin sections (H&E) showing thickening of epidermal and dermal layers, spongiosis, and infiltration of eosinophils (arrows) and mononuclear cells in Tg(+) mice. Scale bars: left and middle panels=100μm, right=20μm. IHC analyses of infiltrating cells (c) MBP+ eosinophils (dark brown). Bar=50μm; (d) F4/80+ cells (brown). Bar=50μm; and (e) CD4+ cells (brown). Bar=50μm. Journal of Investigative Dermatology 2009 129, 742-751DOI: (10.1038/jid.2008.295) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Mast cells and mast-cell mediators in the skin. (a) Toluidine blue staining of skin samples from Tg(-) and Tg(+) mice that were off Dox for 8 weeks. Scale bars: left and middle panels=100μm, right=20μm. (b) Total tissue histamine and (n=7 per group). (c) β-Hexosaminidase content in the skin extracts (n=12 per group). Journal of Investigative Dermatology 2009 129, 742-751DOI: (10.1038/jid.2008.295) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Chemokine mRNA expression in the skin. Total RNA purified from skin samples from K5-tTA-IL-13 Tg(+) mice and Tg(-) controls was analyzed using gene-specific primers. β-Actin gene was used as an internal control. At least two independent experiments were performed for each of the genes. Journal of Investigative Dermatology 2009 129, 742-751DOI: (10.1038/jid.2008.295) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Upregulation of TSLP expression in the skin. (a) RT–PCR for TSLP mRNA in the skin. (b) TSLP protein in the skin extracts (n=6 for each group). (c) IHC identification of cell types expressing TSLP. Skin sections from Tg(+) and Tg(-) mice were stained using anti-TSLP. Bar=50μm. Shown are representative slides of three pairs of stained samples. Journal of Investigative Dermatology 2009 129, 742-751DOI: (10.1038/jid.2008.295) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 IL-13-induced fibrosis and upregulation of TGF-β1. (a) Trichrome staining of skin sections from Tg(+) and Tg(-) mice after Dox off for 8 weeks. Bar=100μm. (b) Quantitative analysis (Sircol Assay) of collagen content in the skin (n=6, each group). (c) TGF-β1 mRNA and (d) TGF-β1 protein (n=6, each group). Journal of Investigative Dermatology 2009 129, 742-751DOI: (10.1038/jid.2008.295) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 7 IL-13-induced increased vasculature and upregulation of VEGF. (a) Increased numbers of blood vessels were present in the skin of Tg(+) mice as compared with that of Tg(-) mice (H&E). Bars: upper panels=200μm and lower panels=50μm. (b) ELISA analysis of VEGF protein in skin extracts (n=6 each group). Journal of Investigative Dermatology 2009 129, 742-751DOI: (10.1038/jid.2008.295) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 8 Dermal expression of IL-13 resulted in altered serum immunoglobulins. Serum samples from Tg(+) and Tg(-) mice off Dox for 8 weeks were collected and analyzed by ELISA. Shown are serum total IgE, IgG1, and IgG2a (n=25 each group). Journal of Investigative Dermatology 2009 129, 742-751DOI: (10.1038/jid.2008.295) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 9 Cytokine production by PBMC and lymphocytes. PBMC and lymphocytes from cutaneous draining lymph nodes were isolated from Tg(+) and Tg(-) mice 8 weeks after Dox withdrawal and stimulated with anti-CD3/CD28 for 3 days in culture. (a) IL-13 and IFN-γ production by peripheral LN CD4+ cells (n=14 per group). (b) IL-13 and IFN-γ production by PBMC (n=5 per group). Journal of Investigative Dermatology 2009 129, 742-751DOI: (10.1038/jid.2008.295) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions