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Human SCGB1A1 protein has been shown to be significantly reduced in BAL, sputum, and serum from humans with asthma as compared with healthy individuals. However, the mechanism of this reduction and its functional impact have not been entirely elucidated. By mining online datasets, we found that the mRNA of SCGB1A1 was significantly repressed in brushed human airway epithelial cells from individuals with asthma, and this repression appeared to be associated with reduced expression of FOXA2. Consistently, both Scgb1A1 and FoxA2 were downregulated in an ovalbumin-induced mouse model of asthma. Furthermore, compared with wild-type mice, Scgb1a1 knockout mice had increased airway hyperreactivity and inflammation when they were exposed to ovalbumin, confirming the antiinflammatory role of Scgb1a1 in protection against asthma phenotypes. To search for potential asthma-related stimuli of SCGB1A1 repression, we tested T-helper cell type 2 cytokines. Both IL-4 and IL-13 repressed epithelial expression of SCGB1A1 and FOXA2. Importantly, infection of epithelial cells with human rhinovirus similarly reduced expression of these two genes, which suggests that FOXA2 may be the common regulator of SCGB1A1. To establish the causal role of reduced FOXA2 in SCGB1A1 repression, we demonstrated that FOXA2 was required for SCGB1A1 expression at baseline. FOXA2 overexpression was sufficient to drive promoter activity and expression of SCGB1A1 and was also able to restore the repressed SCGB1A1 expression in IL-13-treated or rhinovirus-infected cells. Taken together, these findings suggest that low levels of epithelial SCGB1A1 in asthma are caused by reduced FOXA2 expression.

Background and objective: A novel fungal allergen, Alternaria (Alt), has been previously shown to associate with the pathogenesis of allergic rhinitis and bronchial asthma, particularly in arid and semi‐arid regions. Airway epithelial cells are among the first to encounter Alt, and epithelial cytokine production and subsequent airway inflammation are early events in the response to Alt exposure. However, the underlying mechanism is unclear. As protease‐activated receptor 2 (PAR2) has been implicated in most of the Alt‐induced biological events, we investigated the regulation of airway inflammation and epithelial cytokine expression by PAR2. Methods: Wild‐type (WT) and Par2 knockout (Par2‐KO) mice were used to evaluate the in vivo role of PAR2. Primary human and mouse airway epithelial cells were used to examine the mechanistic basis of epithelial cytokine regulation in vitro. Results: Surprisingly, Par2 deficiency had no negative impact on the change of lung function, inflammation and cytokine production in the mouse model of Alt‐induced asthma. Alt‐induced cytokine production in murine airway epithelial cells from Par2‐KO mice was not significantly different from the WT cells. Consistently, PAR2 knockdown in human cells also had no effect on cytokine expression. In contrast, the cytokine expressions induced by synthetic PAR2 agonist or other asthma‐related allergens (e.g. cockroach extracts) were indeed mediated via a PAR2‐dependent mechanism. Finally, we found that EGFR pathway was responsible for Alt‐induced epithelial cytokine expression. Conclusion: The activation of EGFR, but not PAR2, was likely to drive the airway inflammation and epithelial cytokine production induced by Alt. Protease‐activated receptor 2 (PAR2)‐mediated signalling pathway has been implicated in most of the biological activities induced by Alternaria (Alt), an allergen associated with allergic rhinitis and bronchial asthma. Using both in vivo and in vitro models, we have demonstrated that Alt‐induced airway inflammation and epithelial cytokine expression were independent of PAR2 signalling. [ABSTRACT FROM AUTHOR]