Possible new therapeutic strategy to regulate atopic dermatitis through upregulating filaggrin expression - 25/12/13
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.
Le texte complet de cet article est disponible en PDF.Key words : Atopic dermatitis, filaggrin, JTC801, keratinocyte differentiation
Abbreviations used : AD, AP-1, BMDC, CT, FLG, GAPDH, K10, NHEK, ORL1, SC, TCR, TEWL, TGM1
Plan
| Supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology and the Ministry of Health, Labor, and Welfare of Japan and a clinical research grant from the AK project at Kyoto University. |
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| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 133 - N° 1
P. 139 - janvier 2014 Retour au numéro
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