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Interleukin-17A and Transforming Growth Factor-β Regulate microRNA-mediated Airway Smooth Muscle Function in Asthma
AdvisorSinger, Cherie A
Cell and Molecular Pharmacology and Physiology
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Asthma is a chronic inflammatory lung disease characterized by pronounced airway infiltration of immune cells that secrete proinflammatory cytokines, chemokines and growth factors. Most cases of mild to moderate asthma are accompanied by eosinophilic inflammation and respond favorably to β-agonist and glucocorticoid therapy. Severe asthma is a disease subcategorization that develops as a result of heightened, persistent symptoms that generally coincide with pronounced neutrophilic airway inflammation. In severe asthmatics, symptoms are poorly controlled by high-dose inhaled glucocorticoids and often lead to elevated morbidity and mortality rates, which underscores the necessity for novel drug target identification that may overcome limitations in disease management. Many incidences of severe asthma are mechanistically associated with T-helper cell 17 (TH17)-derived cytokines and immune factors that mediate neutrophilic influx to the airways. TH17-secreted interleukin-17A (IL-17A) is an independent risk factor for severe asthma that impacts airway smooth muscle (ASM) remodeling. TH17-derived cytokines and diverse immune mediators further interact with structural cells of the airway to induce pathophysiological processes that impact ASM functionality. Transforming growth factor beta 1 (TGF-β1), a pivotal mediator involved in airway remodeling, correlates with enhanced TH17 activity in severe asthmatics and is essential to TH17 differentiation and IL-17A production. We have previously demonstrated that stimulation of human ASM cells with the proinflammatory stimulus of IL-1β, TNF-α and IFN-γ downregulates microRNA (miR)-25 expression. This was found to alter ASM phenotype via Krüppel-like factor 4 (KLF4) upregulation, while further abrogating airway hyperreactivity in animal models of allergic inflammation. miR-25 is part of the polycistronic miR-106b~25 cluster, whose overexpression is implicated in the development and progression various diseases, including gastric and breast cancer, diabetic neuropathy and myocardial infarction. In the present study, we demonstrate differential regulation of miR-106b~25 between distinct ASM phenotypes and subsequent to independent or cooperative stimulation with IL-17A and TGF-β1. We show for the first time that IL-17A alters TGF-β1-mediated patterns of miRNA and contractile protein expression. Following lentiviral-induced upregulation, we further demonstrate roles of miR-106b~25 in ASM cell proliferation, apoptosis, autophagy and secretion of immunomodulatory mediators. We aim to decipher the roles of dysregulated miRNA-signaling mechanisms of ASM cells in vitro and assess potential implications relevant to in vivo asthmatic ASM function.