STAT6 Links IL-4/IL-13 Stimulation With Pendrin Expression in Asthma and Chronic Obstructive Pulmonary Disease

Abstract

Signaling through the interleukin-4/interleukin-13 (IL-4/IL-13) receptor complex is a crucial mechanism in the development of bronchial asthma and chronic obstructive pulmonary disease (COPD). In bronchial epithelial cells, this signaling pathway leads to changes in the expression levels of several genes that are possibly involved in protection against and/or pathogenesis of these diseases. The expression of pendrin (SLC26A4), a candidate for the latter category, is upregulated by IL-4/IL-13 and leads to overproduction of mucus and increased viscosity of the airway surface liquid (ASL). Therefore, elucidating the transcriptional regulation of pendrin could aid in the development of new pharmacological leads for asthma and/or COPD therapy. Here we show that IL-4/IL-13 significantly increased human pendrin promoter activity in HEK-Blue cells but not in STAT6-deficient HEK293 Phoenix cells; that mutation of the STAT6 binding site (N(4) GAS motif) rendered the promoter insensitive to IL-4/IL-13; and that addition of the N(4) GAS motif to an IL-4/IL-13-unresponsive sequence of the human pendrin promoter conferred sensitivity to both ILs.

Role of Transcription Factors in the Pathogenesis of Asthma and COPD

“…Pendrin-induced expression of MUC5AC, a major mucin in asthma, in bronchial epithelial cells is also STAT6-dependent following activation of the IL-14/IL13 receptor complex (Nakao et al, 2008;Nofziger et al, 2011). The suppressor of cytokine signaling (SOCS) family of proteins down-regulate specifi c cytokine signals (Inoue et al, 2007).…”

Epithelial Anion Transporter Pendrin Contributes to Inflammatory Lung Pathology in Mouse Models of Bordetella pertussis Infection

“…In mouse models of asthma, pendrin upregulation is dependent on the T H 2 cytokines IL-4 and IL-13 acting through the transcription factor STAT6 (34,40). However, these cytokines are not produced at significant levels during B. pertussis infection, and our data rule out STAT6 involvement.…”

“…Lung expression was first identified when an allergy-driven and interleukin-13 (IL-13)-induced upregulation was observed in a murine model of asthma (32). Further studies have gone on to demonstrate that IL-13-stimulated enhanced airway slc26a4 expression is STAT6 dependent and may also be induced by IL-4 (33,34). In a recent publication, slc26a4 was identified as the most highly upregulated gene in human asthmatic bronchi compared with control patients (35).…”

Overexpression of farnesoid X receptor in small airways contributes to epithelial to mesenchymal transition and COX-2 expression in chronic obstructive pulmonary disease

“…The Th 2 cytokines IL-4 and IL-13 are generally known to be the critical mediators in airways hyper-reactivity in asthma. However, both of these cytokines have been demonstrated to be involved in the development and progression of COPD (38). It has been reported that the expression of IL-4 and IL-13 was increased in airways of smokers with chronic bronchitis (39).…”