IL-13 Regulates Cilia Loss and foxj1 Expression in Human Airway Epithelium

Abstract

Mucociliary clearance is essential to the defense mechanisms of the respiratory system. Loss of normal mucociliary clearance contributes to the pathogenesis of genetic and acquired lung diseases. Treatment of cultured differentiated human airway epithelial tissue with IL-13 resulted in a loss of ciliated epithelial cells and an increase in mucus-secreting cells. The loss of ciliated cells was characterized by mislocation of basal bodies and loss of ezrin from the apical cell compartment. In addition to the loss of ciliated cells and increase in mucous cells after IL-13 treatment, cells with characteristics of both ciliated and mucous cells were observed in the airway epithelium. In association with the decrease in ciliated cells after IL-13 treatment, there was noted a decrease in foxj1 expression in the airway epithelium, characterized by a decrease in the number of foxj1-expressing cells. Within the foxj1 promoter, a STAT-binding element was identified and inhibition of foxj1 expression by STAT-6 and IL-13 was demonstrated. These findings suggest molecular and cellular mechanisms for cilia loss in pulmonary disease. Inhibition of foxj1 expression results in loss of apical localization of ezrin and basal bodies with subsequent loss of axonemal structures. These findings have important implications for the pathogenesis and treatment of airway diseases.

Effects of IL-13 on Mucociliary Differentiation of Pediatric Asthmatic Bronchial Epithelial Cells

“…This would suggest that it is via an IL-13 independent effect that our asthmatic cultures are differentiating to this phenotype, which we are currently investigating. The origins of goblet cells are not well understood, although Clara cells (31) and ciliated cells (20,32) have been implicated as goblet cell progenitors, which might explain the increase in goblet cell numbers in our asthmatic cultures. We cannot completely exclude that the difference in unstimulated asthmatic cultures is because of a "carry-over effect" from IL-13 in vivo.…”

NADPH oxidases in lung biology and pathology: Host defense enzymes, and more

“…The differences in DUOX1/2 promoter regions are consistent with the highly variable transcriptional regulation of airway epithelial DUOX1 and DUOX2 in response to pro-inflammatory cytokines or to bacterial or viral stimuli (36,83,96). For example, DUOX1 mRNA expression in primary airway epithelial cultures is induced 3-5 fold by the Th2 cytokines interleukin (IL)-4 and IL-13 (83), which induce ciliatedto-mucus cell transdifferentiation and mucus hyperplasia during allergic airway inflammation (97,98). DUOX1 expression is also dramatically enhanced after hormonal differentiation of fetal lung epithelial cells to alveolar type II cells (90).…”

Ciliated Cells of Pseudostratified Airway Epithelium Do Not Become Mucous Cells after Ovalbumin Challenge

“…Despite their postmitotic state (35)(36)(37), ciliated cells are known to change their shape and gene expression during airway repair (38), suggesting that their behavior may depend on the specific type of injury model used in any given study. Evidence for transdifferentiation of ciliated to mucous cells after IL-13 treatment (23,24), or to squamous cells after naphthaleneinduced injury (38), has been reported. Indeed, a recent study used a lineage tracing strategy in vitro, and suggested that FoxJ1-Cre; EGFP cells give rise to goblet cells in an air-liquid interface platform of epithelial cultures (24).…”

“…In a mouse model of Sendai virus infection, epidermal growth factor receptor (EGFR) activation in ciliated cells inhibited apoptosis and led to the expression of goblet cell markers in these ciliated cells (22). The presence of cells possessing characteristic markers of both ciliated and mucous cells in the mouse and human airway epithelium, in vivo and in vitro, led the authors to postulate that ciliated cells transdifferentiate into mucous cells after IL-13 treatment (22,23). Very recently, Turner and colleagues (24) also suggested that ciliated cells could convert to goblet cells using human airway epithelial cells in culture.…”