IL-18, but Not IL-12, Induces Production of IFN-γ in the Immunosuppressive Environment of HPV16 E7 Transgenic Hyperplastic Skin Christina Gosmann, Ian.

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IL-18, but Not IL-12, Induces Production of IFN-γ in the Immunosuppressive Environment of HPV16 E7 Transgenic Hyperplastic Skin Christina Gosmann, Ian H. Frazer, Stephen R. Mattarollo, Antje Blumenthal Journal of Investigative Dermatology Volume 134, Issue 10, Pages 2562-2569 (October 2014) DOI: 10.1038/jid.2014.201 Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Elevated production of IFN-γ in K14E7 skin compared with wild-type skin. (a) IFN-γ concentrations in wild-type and K14E7 skin homogenates and supernatants of skin explants (four mice per group). Data points indicate individual mice analyzed in at least two independent experiments. (b, c) Flow cytometric analysis of cells isolated from dermis and epidermis of wild-type and K14E7 mice, unstimulated (unstim.) or stimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin. (b) Total live cells gated for CD45.2+IFN-γ+ cells. Plots are representative of four independent experiments (two mice per strain per experiment). (c) Numbers of CD45.2+IFN-γ+ cells in wild-type and K14E7 dermis and epidermis obtained from four independent experiments. Bars indicate means±SEM. (d) IL-6 and IL-1β concentrations in wild-type and K14E7 skin homogenates (four mice per group). ISO, isotype control; NS, not significant; WT, wild type. Journal of Investigative Dermatology 2014 134, 2562-2569DOI: (10.1038/jid.2014.201) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 The majority of IFN-γ-producing cells in K14E7 skin are CD8+ and CD4+ T cells. Flow cytometric analysis of cells isolated from the dermis and epidermis of K14E7 mice, stimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin. (a, b) Percentage of CD3+, CD3+CD8+, and CD3+CD4+ T cells, iNKT cells, and γδ T cells of CD45+IFN-γ+ cells. Plots are representative of four independent experiments (two mice per experiment), for which results are summarized in b. (c) Mean fluorescence intensity of IFN-γ-producing cell subsets from four independent experiments. Bars indicate means±SEM of four independent experiments. Journal of Investigative Dermatology 2014 134, 2562-2569DOI: (10.1038/jid.2014.201) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Elevated IL-12 production in K14E7 skin compared with wild-type skin is dispensable for IFN-γ production. (a) IL-12p70 and IL-12/23p40 concentrations in supernatants of C57BL/6 and K14E7 skin explants following 20 hours of culture (n=4 mice per group). Results are representative of at least two independent experiments. (b, c) IFN-γ concentrations in supernatants of K14E7 skin explants cultured with 10 μg ml-1 isotype, (b) anti-IL12/23p40 antibody, or (c) anti-IL-23p19 antibody (n=6 mice) for 40 hours. Results for individual mice obtained in two independent experiments are shown. (d) IFN-γ concentrations in the supernatants of K14E7 transgenic IL-12p40 heterozygous, IL-12p40-deficient, IFN-γ heterozygous (n=6–7 mice each), or IFN-γ-deficient (n=3 mice) skin explants (ND: below detection limit). Results were obtained in two independent experiments. Bars indicate means±SEM. ISO, isotype control; NS, not significant; WT, wild type. Journal of Investigative Dermatology 2014 134, 2562-2569DOI: (10.1038/jid.2014.201) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 IL-18 production is elevated and induces IFN-γ production in K14E7 skin. (a) IL-18 mRNA expression in C57BL/6 and K14E7 skin (four mice per group). IL-18 concentrations in supernatants of C57BL/6 and K14E7 skin explants (20 hours; four mice per group). Means±SEM are indicated. (a, b) Western blots showing (a) pro-IL-18 (24 kDa), mature IL-18 (18 kDa) (n=3 mice), (b) pro-caspase-1 (45 kDa), and mature caspase-1 (10 kDa) (n=2 mice) in K14E7 skin lysates. β-Actin served as a loading control. Results are representative of at least two independent experiments. (c) IFN-γ concentrations in supernatants of K14E7 skin explants cultured with 10 μg ml-1 isotype or anti-IL-18 and/or anti-IL-12/23p40 antibodies for 40 hours. Data are paired observations for the same mouse, analyzed in two independent experiments (8–9 mice per treatment). ISO, isotype control; WT, wild type. Journal of Investigative Dermatology 2014 134, 2562-2569DOI: (10.1038/jid.2014.201) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions