Immunity, Inflammation and Disease (Sep 2021)

IL‐13 modulates ∆Np63 levels causing altered expression of barrier‐ and inflammation‐related molecules in human keratinocytes: A possible explanation for chronicity of atopic dermatitis

  • Terufumi Kubo,
  • Sayuri Sato,
  • Tokimasa Hida,
  • Tomoyuki Minowa,
  • Yoshihiko Hirohashi,
  • Tomohide Tsukahara,
  • Takayuki Kanaseki,
  • Kenji Murata,
  • Hisashi Uhara,
  • Toshihiko Torigoe

DOI
https://doi.org/10.1002/iid3.427
Journal volume & issue
Vol. 9, no. 3
pp. 734 – 745

Abstract

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Abstract Background Barrier disruption and an excessive immune response in keratinocytes are now considered to have important roles in the pathophysiology of atopic dermatitis (AD). Furthermore, disturbed keratinocyte differentiation is considered to underlie AD. ΔNp63, a p53‐like transcription factor, is a major regulator of keratinocyte differentiation. However, the functional significance of ΔNp63 in AD has not been clarified. Objective In this study, we aimed to investigate the influence of the type 2 inflammatory environment on ΔNp63 expression and AD‐associated molecules regulated by ΔNp63 in keratinocytes. Methods The immunohistochemical expression profiles of ΔNp63 and AD‐related molecules were evaluated in human skin tissue. The function of ΔNp63 in the regulation of AD‐related molecules and the influence of the type 2 inflammatory environment on ΔNp63 expression were investigated using human primary keratinocytes. Expression of ΔNp63 was manipulated using the RNA interfering method. Results In healthy skin tissue, we observed an inverse expression pattern between ∆Np63 and some barrier‐related proteins including filaggrin, caspase‐14, claudin‐1, and claudin‐4. ΔNp63 regulated expression of these genes and proteins. In addition, production of IL‐1β and IL‐33, pro‐inflammatory cytokines, was modulated by ΔNp63. Furthermore, prolonged IL‐13 exposure increased the thickness of the three‐dimensional culture of keratinocytes. IL‐13 interfered with ΔNp63 downregulation during calcium‐induced keratinocyte differentiation. IL‐13 modulated some barrier‐related and inflammation‐related molecules, which were regulated by ΔNp63. Conclusions We have shown that ΔNp63 modulated AD‐related barrier and inflammatory molecules. In addition, ΔNp63 expression was affected by IL‐4/IL‐13. IL‐13–ΔNp63 axis would integrate two major factors of AD pathogenesis: dysregulated barrier and inflammation.

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