Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids

Abstract

Airway inflammation and epithelial remodeling are two key features of asthma. IL-13 and other cytokines produced during T helper type 2 cell-driven allergic inflammation contribute to airway epithelial goblet cell metaplasia and may alter epithelial-mesenchymal signaling, leading to increased subepithelial fibrosis or hyperplasia of smooth muscle. The beneficial effects of corticosteroids in asthma could relate to their ability to directly or indirectly decrease epithelial cell activation by inflammatory cells and cytokines. To identify markers of epithelial cell dysfunction and the effects of corticosteroids on epithelial cells in asthma, we studied airway epithelial cells collected from asthmatic subjects enrolled in a randomized controlled trial of inhaled corticosteroids, from healthy subjects and from smokers (disease control). By using gene expression microarrays, we found that chloride channel, calciumactivated, family member 1 (CLCA1), periostin, and serine peptidase inhibitor, clade B (ovalbumin), member 2 (serpinB2) were up-regulated in asthma but not in smokers. Corticosteroid treatment down-regulated expression of these three genes and markedly up-regulated expression of FK506-binding protein 51 (FKBP51). Whereas high baseline expression of CLCA1, periostin, and serpinB2 was associated with a good clinical response to corticosteroids, high expression of FKBP51 was associated with a poor response. By using airway epithelial cells in culture, we found that IL-13 increased expression of CLCA1, periostin, and serpinB2, an effect that was suppressed by corticosteroids. Corticosteroids also induced expression of FKBP51. Taken together, our findings show that airway epithelial cells in asthma have a distinct activation profile and identify direct and cell-autonomous effects of corticosteroid treatment on airway epithelial cells that relate to treatment responses and can now be the focus of specific mechanistic studies.gene expression microarray ͉ serpinB2 ͉ CLCA1 ͉ FKBP51

Cigarette smoke differentially affects IL-13-induced gene expression in human airway epithelial cells

“…However, we focused on IL‐13 because it has been well described that the gene expression pattern observed in airway epithelial cells from patients with allergic asthma is well reflected by IL‐13 treatment of cultured primary airway epithelial cells (Woodruff et al. 2007, 2009). …”

“…A Th2‐high subtype of asthma has been described and is associated with increased bronchial epithelial expression of periostin ( POSTN ), serpin B2 ( SERPINB2 ), and chloride channel regulator 1 ( CLCA1 ), and predicts a beneficial therapeutic response to corticosteroids (Woodruff et al. 2007, 2009). Recently various clinical trials have shown the potential of inhibitors of Th2 inflammation, including monoclonal antibodies against interleukin (IL)‐13, to modulate clinical outcomes in asthma (van Buul and Taube 2015).…”

“…2002; Woodruff et al. 2007). IL‐13 is an important mediator for the induction of goblet cell metaplasia in Th2‐mediated asthma and is a central regulator in the epithelial expression of POSTN , SERPINB2 , and CLCA1 (Woodruff et al.…”

“…IL‐13 is an important mediator for the induction of goblet cell metaplasia in Th2‐mediated asthma and is a central regulator in the epithelial expression of POSTN , SERPINB2 , and CLCA1 (Woodruff et al. 2007). Periostin, the protein encoded by the POSTN gene, is of particular interest as a biomarker, as it is detectable in the circulation and may be useful as a blood biomarker for IL‐13‐activated bronchial epithelial cells.…”

Improving the diagnosis of eosinophilic asthma

“…Several reports have shown significant correlations between periostin in serum and eosinophils in sputum [42,43]. Woodruff et al were the first to show upregulated periostin gene expression in bronchoalveolar lavage from patients with asthma as compared to normal control subjects, which was associated with increased concentrations of IL-4, IL-5, and IL-13 [44]. These patients also had higher eosinophil counts in lavage fluid, suggesting that increased periostin levels might reflect a Th2-high profile.…”