Atsushi Otsuka1, Hiromi Doi2, Gyohei Egawa2, Akiko Maekawa3, Tomoko Fujita3, Satoshi Nakamizo2, Chisa Nakashima2, Saeko Nakajima2, Takeshi Watanabe4, Yoshiki Miyachi2, Shuh Narumiya3, Kenji Kabashima5. 1. Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Center for Innovation in Immunoregulative Technology and Therapeutics, Kyoto University Graduate School of Medicine, Kyoto, Japan. 2. Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan. 3. Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan. 4. Center for Innovation in Immunoregulative Technology and Therapeutics, Kyoto University Graduate School of Medicine, Kyoto, Japan. 5. Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan. Electronic address: kaba@kuhp.kyoto-u.ac.jp.
Abstract
BACKGROUND: Nonsense mutations in filaggrin (FLG) represent a significant genetic factor in the cause of atopic dermatitis (AD). OBJECTIVE: It is of great importance to find drug candidates that upregulate FLG expression and to determine whether increased FLG expression controls the development of AD. METHODS: We screened a library of bioactives by using an FLG reporter assay to find candidates that promoted FLG mRNA expression using a human immortalized keratinocyte cell line (HaCaT). We studied the effect of the compound on keratinocytes using the human skin equivalent model. We examined the effect of the compound on AD-like skin inflammation in NC/Nga mice. RESULTS: JTC801 promoted FLG mRNA and protein expression in both HaCaT and normal human epidermal keratinocytes. Intriguingly, JTC801 promoted the mRNA and protein expression levels of FLG but not the mRNA levels of other makers for keratinocyte differentiation, including loricrin, keratin 10, and transglutaminase 1, in a human skin equivalent model. In addition, oral administration of JTC801 promoted the protein level of Flg and suppressed the development of AD-like skin inflammation in NC/Nga mice. CONCLUSION: This is the first observation that the compound, which increased FLG expression in human and murine keratinocytes, attenuated the development of AD-like skin inflammation in mice. Our findings provide evidence that modulation of FLG expression can be a novel therapeutic target for AD.
BACKGROUND: Nonsense mutations in filaggrin (FLG) represent a significant genetic factor in the cause of atopic dermatitis (AD). OBJECTIVE: It is of great importance to find drug candidates that upregulate FLG expression and to determine whether increased FLG expression controls the development of AD. METHODS: We screened a library of bioactives by using an FLG reporter assay to find candidates that promoted FLG mRNA expression using a human immortalized keratinocyte cell line (HaCaT). We studied the effect of the compound on keratinocytes using the human skin equivalent model. We examined the effect of the compound on AD-like skin inflammation in NC/Nga mice. RESULTS:JTC801 promoted FLG mRNA and protein expression in both HaCaT and normal human epidermal keratinocytes. Intriguingly, JTC801 promoted the mRNA and protein expression levels of FLG but not the mRNA levels of other makers for keratinocyte differentiation, including loricrin, keratin 10, and transglutaminase 1, in a human skin equivalent model. In addition, oral administration of JTC801 promoted the protein level of Flg and suppressed the development of AD-like skin inflammation in NC/Nga mice. CONCLUSION: This is the first observation that the compound, which increased FLG expression in human and murine keratinocytes, attenuated the development of AD-like skin inflammation in mice. Our findings provide evidence that modulation of FLG expression can be a novel therapeutic target for AD.
Authors: Michiko K Oyoshi; Hans C Oettgen; Talal A Chatila; Raif S Geha; Paul J Bryce Journal: J Allergy Clin Immunol Date: 2014-02 Impact factor: 10.793