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.


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.


CONCLUSIONS
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.
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.
Atsushi
A
Otsuka
Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Hiromi
H
Doi
Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Gyohei
G
Egawa
Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Akiko
A
Maekawa
Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Tomoko
T
Fujita
Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Satoshi
S
Nakamizo
Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Chisa
C
Nakashima
Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Saeko
S
Nakajima
Center for Innovation in Immunoregulative Technology and Therapeutics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Takeshi
T
Watanabe
Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Yoshiki
Y
Miyachi
Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Shuh
S
Narumiya
Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan. Electronic address: kaba@kuhp.kyoto-u.ac.jp.
Kenji
K
Kabashima
D000634:Aminoquinolines / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage* / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002461:Cell Line, Transformed; D018389:Codon, Nonsense / Q000235:genetics; D003876:Dermatitis, Atopic / Q000235:genetics* / Q000628:therapy; D000091344:Filaggrin Proteins; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism*; D053550:Keratin-10 / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects* / Q000276:immunology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D058990:Molecular Targeted Therapy; D018847:Opioid Peptides / Q000037:antagonists & inhibitors; D011503:Transglutaminases / Q000378:metabolism; D015854:Up-Regulation; D000097629:Nociceptin
D000634:Aminoquinolines; D001549:Benzamides; D018389:Codon, Nonsense; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D053550:Keratin-10; D008565:Membrane Proteins; D018847:Opioid Peptides; D011503:Transglutaminases; D000097629:Nociceptin; C000717249:FLG protein, human; C433236:N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl)benzamide; C064554:loricrin; C105804:transglutaminase 1
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