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

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.

Generation of self-replicating airway organoids from the cave nectar bat Eonycteris spelaea as a model system for studying host–pathogen interactions in the bat airway epithelium

“…IL-13 treatment also had a small but significant increase in TP63 expression. IL-13 has been previously reported to modulate P63 expression during human keratinocyte differentiation [ 20 ]. Further work is warranted to identify why the basal differentiation medium was not sufficient to induce goblet cell differentiation in bat AECs.…”

Type 2 Inflammation Drives an Airway Basal Stem Cell Program Through Insulin Receptor Substrate Signaling

“…TP63 was previously reported to be induced by the T2 cytokine IL-13 in human keratinocytes (58), thus we hypothesized that BCAM and TP63 may be similarly regulated in the sinonasal mucosa. First, we assessed BCAM and TP63 expression in bulk RNA-seq of sinonasal BCs from CRSwNP, a T2 high disease, and from non-polyp controls (CRSsNP).…”

Cisplatin‐induced HSF1‐HSP90 axis enhances the expression of functional PD‐L1 in oral squamous cell carcinoma

“…The protocol for western blot analysis has been described elsewhere. 16 The following antibodies were used: rabbit anti‐PD‐L1 monoclonal antibody (mAb) (clone 28‐8; Abcam) rabbit anti‐HSP27 polyclonal antibody (ab5579; Abcam), mouse anti‐HSP70 mAb (clone C92F3A‐5; Abcam), rabbit anti‐HSP90 polyclonal antibody (#4874; Cell Signaling Technology, Danvers, MA), rabbit antiheat shock factor (HSF) 1 mAb (clone EP1710Y; Abcam), rabbit anti‐HSF1 phospho S326 mAb (clone EP1713Y; Abcam), rabbit anti‐HSF1 phospho S320 mAb (clone EPR1712; Abcam), and anti‐β‐actin mAb (clone AC‐15; Sigma‐Aldrich). Peroxidase‐conjugated goat antimouse and antirabbit IgGs were purchased from KPL.…”