Possible new therapeutic strategy to regulate atopic dermatitis through upregulating filaggrin expression

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....

Full description

Saved in:
Bibliographic Details
Published in:Journal of allergy and clinical immunology 2014-01, Vol.133 (1), p.139-146.e10
Main Authors: Otsuka, Atsushi, MD, PhD, Doi, Hiromi, MS, Egawa, Gyohei, MD, PhD, Maekawa, Akiko, PhD, Fujita, Tomoko, MD, PhD, Nakamizo, Satoshi, MD, Nakashima, Chisa, MD, Nakajima, Saeko, MD, PhD, Watanabe, Takeshi, MD, PhD, Miyachi, Yoshiki, MD, PhD, Narumiya, Shuh, MD, PhD, Kabashima, Kenji, MD, PhD
Format: Article
Language:English
Subjects:
Allergic diseases
Allergy and Immunology
Aminoquinolines - administration & dosage
Aminoquinolines - pharmacology
Animals
Atopic dermatitis
Benzamides - administration & dosage
Benzamides - pharmacology
Biological and medical sciences
Cell Differentiation - drug effects
Cell Line, Transformed
Cellulose
Cloning
Codon, Nonsense - genetics
Cyclin-dependent kinases
Dermatitis, Atopic - genetics
Dermatitis, Atopic - therapy
filaggrin
Filaggrin Proteins
Fundamental and applied biological sciences. Psychology
Fundamental immunology
Humans
Hydration
Immunopathology
Intermediate Filament Proteins - genetics
Intermediate Filament Proteins - metabolism
JTC801
Keratin
Keratin-10 - metabolism
keratinocyte differentiation
Keratinocytes - drug effects
Keratinocytes - immunology
Medical sciences
Membrane Proteins - metabolism
Mice
Mice, Inbred Strains
Molecular Targeted Therapy
Mutation
Nociceptin
Opioid Peptides - antagonists & inhibitors
Proteins
Rodents
Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis
Skin allergic diseases. Stinging insect allergies
Transglutaminases - metabolism
Up-Regulation
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0091-6749
1097-6825
DOI:10.1016/j.jaci.2013.07.027