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Possible new therapeutic strategy to regulate atopic dermatitis through upregulating filaggrin expression  Atsushi Otsuka, MD, PhD, Hiromi Doi, MS, Gyohei.

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Presentation on theme: "Possible new therapeutic strategy to regulate atopic dermatitis through upregulating filaggrin expression  Atsushi Otsuka, MD, PhD, Hiromi Doi, MS, Gyohei."— Presentation transcript:

1 Possible new therapeutic strategy to regulate atopic dermatitis through upregulating filaggrin expression  Atsushi Otsuka, MD, PhD, Hiromi Doi, MS, Gyohei Egawa, MD, PhD, Akiko Maekawa, PhD, Tomoko Fujita, MD, PhD, Satoshi Nakamizo, MD, Chisa Nakashima, MD, Saeko Nakajima, MD, PhD, Takeshi Watanabe, MD, PhD, Yoshiki Miyachi, MD, PhD, Shuh Narumiya, MD, PhD, Kenji Kabashima, MD, PhD  Journal of Allergy and Clinical Immunology  Volume 133, Issue 1, Pages e10 (January 2014) DOI: /j.jaci Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 JTC801 promotes the transcription level of FLG. A, mRNA levels of FLG using NHEKs after 1 day. B, Relative activity of FLG was examined by using NHEKs after 1- and 3-day incubations with high Ca2+ levels, Scriptaid, or JTC801. C, Relative activity of FLG was evaluated in the presence of IL-4 and IL-13 after a 3-day incubation. D, Morphology of NHEKs after a 3-day incubation under conditions of high Ca2+ or JTC801. *P < .05. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 The AP-1 lesion is a main sequence of JTC801-dependent FLG expression. A and B, Relative activity of FLG was examined by using transfected NHEKs (1.5 K [−1504bp], 0.9 K [−980bp], 0.2 K [−246bp], and AP-1 deleted). C, Relative activity of FLG was examined by using transfected HeLa cells after a 3-day incubation. *P < .05. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 JTC801 promotes expression levels of the FLG monomer in the human skin equivalent model. A, mRNA levels of FLG, Ki67, loricrin (Lor), K10, and TGM1 in the human skin equivalent model after a 5-day incubation in the presence of JTC801. B, Western blot analysis for FLG expression at several concentrations of JTC801 (from left: 0, 0.01 nmol/L, 0.1 nmol/L, 1 nmol/L, 10 nmol/L, 100 nmol/L, and 1 μmol/L). These results are representative of 2 independent experiments. FG, Filaggrin; Lor, loricrin; PFG, profilaggrin. C, FLG expression with human skin organ culture by means of immunohistochemistry under JTC801 conditions or not. *P < .05. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 JTC801 promotes the expression level of Flg by using flaky tail mice. A, Western blot analysis of Flg expression in skin injected with JTC801 subcutaneously. +/−, Heterozygous deficient flaky tail mouse; −/−, homozygous deficient flaky tail mouse. B, TEWL and skin conductance were measured in this model. *P < .05. FG, Filaggrin; PFG, profilaggrin. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 5 JTC801 attenuated atopic skin inflammation with NC/Nga mice. A, Western blot analysis of Flg expression in the lesional (+) or control (−) skin of NC/Nga mice. B, TEWL and skin conductance were measured after administration of JTC801 for 2 weeks. C, Time course of total clinical severity scores (left panel) and clinical photographs of NC/Nga mice after 6 weeks of administration of JTC801 (right panel). D, Western blot analysis of Flg expression with these mice. E, Relative density of the FLG monomer to GAPDH. Data in Fig 5, B, are presented as means ± SDs, and those in Fig 5, C and E, are presented as means ± SEMs. FG, Filaggrin; PFG, profilaggrin. *P < .05. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig E1 Relative activity of FLG was examined by using NHEKs after 5-day incubation with high Ca2+ levels, Scriptaid, or JTC801. *P < .05. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig E2 Western blot analysis for FLG with NHEKs. Western blot analysis for FLG expression under several concentrations of JTC801 (from left: 0, 10, and 1000 nmol/L) is shown. These results are representative of 3 independent experiments. FG, Filaggrin; PFG, profilaggrin. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Fig E3 Effects of JTC801 on development of tight junction and immune cell functions. A, mRNA levels of claudin-1 of NHEKs for a 3-day incubation with or without JTC801. B, Numbers of total T cells, CD4+ T cells, CD8+ T cells, IFN-γ+ cells, and IL-4+ cells with or without JTC801 (1, 10, and 100 nmol/L). C, Flow cytometric histogram of CD80 and CD86 on BMDCs in the presence or absence of JTC801. These results are a representative of 2 independent experiments. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

10 Fig E4 Immunohistochemistry of TCR+, CD45R+, and MHC class II+ cells. A, Immunohistochemistry of TCR+, CD45R+, and MHC class II+ cells with or without the treatment of JTC801 in the lesional skin of NC/Nga mice. Scale bar = 50 μm. B, Numbers of TCR+, CD45R+, and MHC class II+ cells per field (n = 5). All data are presented as the mean ± SD and are representative of 2 experiments. *P < .05. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

11 Fig E5 Concentrations of JTC801 in serum. Serum concentrations of JTC801 were measured 0.5, 1, 2, 4, 6, and 8 hours after the oral administration of 1 or 10 mg/mL JTC801. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

12 Fig E6 Histology of nonlesional skin in mice treated with or without JTC801. Scale bar = 100 μm. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

13 Fig E7 Scratching behavior in NC/Nga mice. The number of scratching sessions for 22 hours after JTC801 (30 mg/kg in 0.5% methyl cellulose) or vehicle treatment (n = 10) is shown. These results are a representative of 2 independent experiments. N.S., Not significant. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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