The Janus kinase inhibitor JTE-052 improves skin barrier function through suppressing signal transducer and activator of transcription 3 signaling

详细信息    查看全文

• 作者：Wataru Amano ; DVM^a ; ^b ; Saeko Nakajima ; MD ; PhD^a ; Hayato Kunugi ; PhD^b ; Yasuharu Numata ; MS^b ; Akihiko Kitoh ; MD ; PhD^a ; Gyohei Egawa ; MD ; PhD^a ; Teruki Dainichi ; MD ; PhD^a ; Tetsuya Honda ; MD ; PhD^a ; Atsushi Otsuka ; MD ; PhD^a ; Yukari Kimoto ; MS^b ; Yasuo Yamamoto ; MS^b ; Atsuo Tanimoto ; MS^b ; Mutsuyoshi Matsushita ; PhD^b ; ^{mutsuyoshi.matsushita@jt.com" class="auth_mail" title="E-mail the corresponding author} ; Yoshiki Miyachi ; MD ; PhD^a ; Kenji Kabashima ; MD ; PhD^a ; ^c ; ^{kaba@kuhp.kyoto-u.ac.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Atopic dermatitis ; filaggrin ; signal transducer and activator of transcription 3 ; Janus kinase inhibitor ; keratinocyte differentiation
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2015
• 出版时间：September 2015
• 年：2015
• 卷：136
• 期：3
• 页码：667-677.e7
• 全文大小：2767 K

文摘

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.

Objectives

Taking into account the fact that the T_H2 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.

Conclusion

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.