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.
Keywords: AD; AP-1; Activator protein 1; Atopic dermatitis; BMDC; Bone marrow–derived dendritic cell; C(T); Cycle threshold; FLG; Filaggrin; GAPDH; Glyceraldehyde-3-phosphate dehydrogenase; JTC801; K10; Keratin 10; NHEK; Normal human epidermal keratinocyte; ORL1; Opioid receptor-like 1; SC; Stratum corneum; T-cell receptor; TCR; TEWL; TGM1; Transepidermal water loss; Transglutaminase 1; filaggrin; keratinocyte differentiation.
Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.