IL-17A Mediates a Selective Gene Expression Profile in Asthmatic Human Airway Smooth Muscle Cells

Abstract

Airway smooth muscle (ASM) cells are thought to contribute to the pathogenesis of allergic asthma by orchestrating and perpetuating airway inflammation and remodeling responses. In this study, we evaluated the IL-17RA signal transduction and gene expression profile in ASM cells from subjects with mild asthma and healthy individuals. Human primary ASM cells were treated with IL-17A and probed by the Affymetrix GeneChip array, and gene targets were validated by real-time quantitative RT-PCR. Genomic analysis underlined the proinflammatory nature of IL-17A, as multiple NF-κB regulatory factors and chemokines were induced in ASM cells. Transcriptional regulators consisting of primary response genes were overrepresented and displayed dynamic expression profiles. IL-17A poorly enhanced IL-1β or IL-22 gene responses in ASM cells from both subjects with mild asthma and healthy donors. Interestingly, protein modifications to the NF-κB regulatory network were not observed after IL-17A stimulation, although oscillations in IκBε expression were detected. ASM cells from subjects with mild asthma up-regulated more genes with greater overall variability in response to IL-17A than from healthy donors. Finally, in response to IL-17A, ASM cells displayed rapid activation of the extracellular signal-regulated kinase/ribosomal S6 kinase signaling pathway and increased nuclear levels of phosphorylated extracellular signal-regulated kinase. Taken together, our results suggest that IL-17A mediated modest gene expression response, which, in cooperation with the NF-κB signaling network, may regulate the gene expression profile in ASM cells.

Endoplasmic Reticulum Stress and Mitochondrial Function in Airway Smooth Muscle

“…As a result, overexpression of Mfn2 in vascular smooth muscle inhibits cell proliferation (Liesa et al, 2009;Antico Arciuch et al, 2012). Importantly, ERK1/2 activation is believed to play a critical role in hASM proliferation induced by inflammatory cytokines (Lee et al, 2001;Kip et al, 2005;Yu et al, 2013;Dragon et al, 2014;Movassagh et al, 2014). While the relation between ER stress and Mfn2 is not clearly established, studies suggest that ER stress induces cell proliferation in many cell types (Vandewynckel et al, 2013;Chen et al, 2018).…”

NF-kappaB Signaling in Chronic Inflammatory Airway Disease

“…Th17 cytokines have an important role in neutrophil recruitment, and contribute to structural changes in bronchial epithelial and airway smooth muscle (ASM) cells [ 67 ]. The actions of IL-17 and/or IL-22 in epithelial mucin production and ASM cell proliferation involve NF-κB signaling [ 68 , 69 , 70 ].…”

Interaction between endoplasmic/sarcoplasmic reticulum stress (ER/SR stress), mitochondrial signaling and Ca2+ regulation in airway smooth muscle (ASM)

“…In addition, Mfn2 may inhibit the activation of pro-proliferative kinases such as extracellular signal-regulated kinase (ERK1/2) (Liesa et al 2009). Importantly, many studies suggest that ERK1/2 activation plays a critical role in mediating ASM proliferation (Lee et al 2001; Yu et al 2013; Dragon et al 2014;Movassagh et al 2014). …”