title: The Janus kinase inhibitor JTE-052 improves skin barrier function through suppressing signal transducer and activator of transcription 3 signaling.
abstract: BACKGROUND
  Barrier disruption and the resulting continuous exposure to allergens are presumed to be responsible for the development of atopic dermatitis (AD). However, the mechanism through which skin barrier function is disrupted in patients with AD remains unclear.
  
  
  OBJECTIVE
  Taking into account the fact that the TH2 milieu impairs keratinocyte terminal differentiation, we sought to clarify our hypothesis that the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays a critical role in skin barrier function and can be a therapeutic target for AD.
  
  
  METHODS
  We analyzed the mechanism of keratinocyte differentiation using a microarray and small interfering RNA targeting STATs. We studied the effect of the JAK inhibitor JTE-052 on keratinocyte differentiation using the human skin equivalent model and normal human epidermal keratinocytes. We applied topical JAK inhibitor onto NC/Nga mice, dry skin model mice, and human skin grafted to immunocompromised mice.
  
  
  RESULTS
  IL-4 and IL-13 downregulated genes involved in keratinocyte differentiation. STAT3 and STAT6 are involved in keratinocyte differentiation and chemokine production by keratinocytes, respectively. Topical application of the JAK inhibitor suppressed STAT3 activation and improved skin barrier function, permitting increases in levels of terminal differentiation proteins, such as filaggrin, and natural moisturizing factors in models of AD and dry skin and in human skin.
  
  
  CONCLUSIONS
  STAT3 signaling is a key element that regulates keratinocyte differentiation. The JAK inhibitor can be a new therapeutic tool for the treatment of disrupted barrier function in patients with AD.
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Central Pharmaceutical Research Institute, Japan Tobacco, Tokyo, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Amano
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Saeko
authors.initials: S
authors.lastname: Nakajima
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco, Tokyo, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Kunugi
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco, Tokyo, Japan.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Numata
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kitoh
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Gyohei
authors.initials: G
authors.lastname: Egawa
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Teruki
authors.initials: T
authors.lastname: Dainichi
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Honda
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Otsuka
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco, Tokyo, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Kimoto
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco, Tokyo, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco, Tokyo, Japan.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Tanimoto
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco, Tokyo, Japan. Electronic address: mutsuyoshi.matsushita@jt.com.
authors.forename: Mutsuyoshi
authors.initials: M
authors.lastname: Matsushita
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Miyachi
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan; PRESTO, Japan Science and Technology Agency, Saitama, Japan. Electronic address: kaba@kuhp.kyoto-u.ac.jp.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kabashima
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D003876:Dermatitis, Atopic / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D000091344:Filaggrin Proteins; D005786:Gene Expression Regulation; D006801:Humans; D016867:Immunocompromised Host; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000276:immunology; D015603:Keratinocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D050800:STAT6 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D016038:Skin Transplantation; D017768:Skin, Artificial; D014183:Transplantation, Heterologous
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D018793:Interleukin-13; D007381:Intermediate Filament Proteins; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D050800:STAT6 Transcription Factor; C494087:Stat3 protein, mouse; C494100:Stat6 protein, mouse; D015847:Interleukin-4
keywords: Atopic dermatitis; Janus kinase inhibitor; filaggrin; keratinocyte differentiation; signal transducer and activator of transcription 3