IL‑17A and GDF15 are able to induce epithelial‑mesenchymal transition of lung epithelial cells in response to cigarette smoke

Abstract

Smoking is one of the primary causes of chronic obstructive pulmonary disease (COPD). Sustained active epithelial-mesenchymal transition (EMT) in COPD may explain the core pathophysiology of airway fibrosis and why lung cancer is so common among smokers. Interleukin (IL)-17A and growth/differentiation factor (GDF)15 have been reported to be biomarkers of COPD; however, the role of IL-17A and GDF15 in EMT remains unclear. The aim of the present study was to investigate the role of IL-17A and GDF15 in the pathogenesis of COPD. It was demonstrated that IL-17A and GDF15 are upregulated in patients with COPD, particularly those with a history of smoking. The results also revealed that IL-17A and GDF15 expression was negatively correlated with the epithelial marker epithelial-cadherin and positively correlated with the mesenchymal marker vimentin. Furthermore, treatment with cigarette smoke extract or IL-17A induced GDF15 expression. Combined treatment with IL-17A and GDF15 induced EMT in human small epithelial HSAEpiC cells in vitro. Collectively, the results of the present study suggest that IL-17A and GDF15-induced EMT serves an important role in the pathology of COPD.

Growth differentiation factor 15 in adverse cardiac remodelling: from biomarker to causal player

“…These data support the notion that GDF15 has a potential anti‐migratory effect on endothelial cells 128 . However, contradictory results are found that display EndMT progression and increased cell migration promoted by GDF15, through activation of the TGF‐β pathway in a paracrine and autocrine signalling manner 93,129,130 …”

Screening of Cellular Stress Responses Induced by Ambient Aerosol Ultrafine Particle Fraction PM0.5 in A549 Cells

“…EGR1 has been shown to be induced by cigarette smoke in lung cells, which again documents its association with AhR activation, and with chemokine production, MAPK activation, HSP70 signaling and with inflammatory responses [41][42][43][44]. GDF15 has been reported in the airway epithelium of smokers with chronic obstructive pulmonary disease and in human airway epithelial cells exposed to cigarette smoke [45]. A possible link between mixed AhR/p53 activation and induced levels of cellular stress markers EGR1 and GDF15 is also strongly supported by OTFBS (overrepresented transcription factor binding sites) analysis of human EGR1 and GDF15 genes ( Table 2) as the binding site matrices for both transcription factors are significantly predicted in regulatory regions of GDF15 gene.…”

Role of Growth Differentiation Factor 15 in Lung Disease and Senescence: Potential Role Across the Lifespan

“…Promotes proliferation and differentiation in fetal lung development (19) Maternal serum levels increase throughout during pregnancy (12) High serum levels in term neonates that decline postnatally (20) Upregulated in neonatal mice exposed to hyperoxia in vivo (21) Upregulated in pulmonary epithelial and endothelial cells exposed to hyperoxia (22) GDF15 loss leads to decreased cell viability and increased oxidative stress (23) Chronic Obstructive Pulmonary Disease (COPD) Higher serum levels are associated with increased morbidity and mortality (4,24) Mediates smoking-induced inflammation and cellular senescence (25)(26)(27) Promotes mucin production in ciliated epithelial cells (28) Exacerbates lung inflammation secondary to infection (29) Contributes to cachexia: GFRAL mediated signaling, induces lipolysis and promotes muscle wasting (30)(31)(32)(33) Pulmonary Hypertension (PH) Associated with prognosis and response to therapy (34)(35)(36) Levels increased in pediatric PH related to congenital heart disease (37) Associated with increase in right atrial and pulmonary capillary wedge pressure (34) Induces muscle atrophy that is reversed by TAK1 inhibitor (38) Promotes angiogenesis and hinders endothelial cell apoptosis (39,40) Lung Fibrosis Associated with disease severity (41) Associated with higher odds of interstitial lung abnormality (42) Activates fibroblasts and M2 macrophages (40) Prevents the activation of fibroblasts during lung remodeling (43) FIGURE 1 | Cellular senescence and lung disease across the lifespan: role of GDF15.…”

“…Cigarette smoking is the leading cause and the single most significant risk factor for developing COPD ( 62 ). In human small airway epithelial cells, cigarette smoke (CS) extract induces GDF15 expression ( 25 ). CS increases GDF15 expression in humans with and without COPD and in murine models for COPD ( 26 ).…”

“…Significantly, deletion of the GDF15 gene in mice led to attenuation of CS related pulmonary inflammation ( 26 ). GDF15 also plays an important role in airway mucosal immunity as it promotes mucin production via activation of phosphoinositide 3-kinase (PI3K) in the ciliated epithelial cells ( 25 , 28 , 63 ). CS-induction of GDF15 also promotes cellular senescence through the activin receptor-like kinase 1/Smad1 pathway and increases expression of cellular senescence markers including p21, p16, and high-mobility group box 1 (HMGB1) in airway epithelial cells ( 27 ).…”