IL-13 Inhibits Multicilin Expression and Ciliogenesis via Janus Kinase/Signal Transducer and Activator of Transcription Independently of Notch Cleavage

Abstract

Loss of ciliated cells and increases in goblet cells are seen in respiratory diseases such as asthma. These changes result in part from reduced differentiation of basal progenitor cells to ciliated cells during injury and repair. The T helper 2 cytokine, IL-13, has been shown to inhibit ciliated cell differentiation, but the mechanism is not clearly understood. We recently showed that Notch signaling inhibits ciliated cell differentiation in submerged culture by repressing multicilin and forkhead box J1 (FOXJ1) expression, genes required for ciliogenesis. Using a novel method to study ciliated cell differentiation, we investigated the relationship between IL-13 and Notch signaling pathways. We found that IL-13 inhibits ciliated cell differentiation by repressing multicilin and FOXJ1 expression but does so independent of Notch signaling. In addition, we show that pharmacological inhibition of Janus kinase/signal transducer and activator of transcription, but not mitogen activated protein kinase kinase, signaling rescues multicilin and FOXJ1 expression and ciliated cell differentiation in the presence of IL-13. These findings indicate that regulation of multicilin expression by two distinct signaling pathways affects ciliated cell differentiation. In addition, the requirement for Janus kinase activation in IL-13-induced inhibition of ciliogenesis provides a potential therapeutic target for the treatment of respiratory disease.

A cellular census of healthy lung and asthmatic airway wall identifies novel cell states in health and disease

“…Conflicting data have been reported on dependence of IL13-induced goblet cell metaplasia on NOTCH signalling in ex vivo cultured PBECs 25,46 . Our data on freshly isolated bronchial epithelial cells show that expression of NOTCH2 and Notch target genes is present in goblet cells from healthy controls only, and absent from ciliated, mucous ciliated and goblet cells in asthmatic airway wall.…”

Phenotypic and genetic aspects of epithelial barrier function in asthmatic patients

“…Because Notch signaling inhibits ciliated cell differentiation in vitro by repressing multicilin and forkhead box J1, 165 low Notch levels might suggest increased ciliogenesis, but this was not the case. However, it has been shown that IL-13 inhibits ciliated cell differentiation independent of Notch signaling, 166 suggesting 2 distinct signaling pathways can affect ciliated cell differentiation, which might be of relevance in the different SCs of severe asthma. The other SCs showed some overlap with SC2, but each exhibited distinct profiles illustrating the heterogeneity of the epithelial gene signature across the spectrum of asthma severity.…”

Persistent induction of goblet cell differentiation in the airways: Therapeutic approaches

“…In contrast to this finding, the overexpression of either Notch1 or Notch3 has been shown to drive goblet cell metaplasia in a system devoid of inflammatory cytokines such as IL-13 (Gomi, Arbelaez, Crystal, & Walters, 2015). This indicates that different Notch isoforms impact on GCD both within IL-13-high and IL-13-low environments (Gerovac & Fregien, 2016;Gomi et al, 2015;Guseh et al, 2009).…”

“…Binding of the NICD to RBPJ is well documented to activate the transcriptional repressors hairy and enhancer-of-split (HES) and hairy and enhancer-ofsplit related with YRPW motif (HEY) (Fischer & Gessler, 2007), which repress airway ciliogenesis (Gerovac et al, 2014;Tsao et al, 2009). Notch signaling also represses expression of multicilin (MCIDAS) and forkhead box J1 (FOXJ1) in airway epithelium, which in turn inhibits ciliated cell differentiation (Gerovac et al, 2014;Gerovac & Fregien, 2016). Additionally, recent cell lineage tracing studies have highlighted Notch as a key regulator of epithelial trans-differentiation in the adult lung (Lafkas et al, 2015).…”