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Role of IL-17A in murine models of COPD airway disease
American Journal of Physiology-Lung Cellular and Molecular Physiology, 2016
Small airway fibrosis is a major pathological feature of chronic obstructive pulmonary disease (COPD) and is refractory to current treatments. Chronic inflammatory cells accumulate around small airways in COPD and are thought to play a major role in small airway fibrosis. Mice deficient in α/β T cells have recently been shown to be protected from both experimental airway inflammation and fibrosis. In these models, CD4+Th17 cells and secretion of IL-17A are increased. However, a pathogenic role for IL-17 in specifically mediating fibrosis around airways has not been demonstrated. Here a role for IL-17A in airway fibrosis was demonstrated using mice deficient in the IL-17 receptor A ( il17ra). Il17ra-deficient mice were protected from both airway inflammation and fibrosis in two different models of airway fibrosis that employ COPD-relevant stimuli. In these models, CD4+ Th17 are a major source of IL-17A with other expressing cell types including γδ T cells, type 3 innate lymphoid cell...
Chest, 2010
A sthma and COPD are common conditions that account for substantial morbidity and mortality worldwide. Asthma affects 5% to 10% of adults, of whom 10% have severe disease. 1,2 Severe asthma represents a disproportionate health-care burden as it leads to debilitating chronic symptoms despite optimal standard asthma treatment and contributes to more than half of the health-care costs attributed to asthma. 1-4 COPD is predicted to be the third leading cause of death in 2030. 5,6 Both conditions are charac-terized by airfl ow obstruction with airway infl ammation and remodeling.
Th17 cytokines: novel potential therapeutic targets for COPD pathogenesis and exacerbations
European Respiratory Journal, 2017
Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease of the airways caused mainly by cigarette smoke exposure. COPD progression is marked by exacerbations of the disease, often associated with infections. Recent data show the involvement in COPD pathophysiology of interleukin (IL)-17 and IL-22, two cytokines that are important in the control of lung inflammation and infection. During the initiation and progression of the disease, increased IL-17 secretion causes neutrophil recruitment, leading to chronic inflammation, airways obstruction and emphysema. In the established phase of COPD, a defective IL-22 response facilitates pathogen-associated infections and disease exacerbations. Altered production of these cytokines involves a complex network of immune cells and dysfunction of antigen-presenting cells. In this review, we describe current knowledge on the involvement of IL-17 and IL-22 in COPD pathophysiology at steady state and during exacerbations, and d...
Respiratory Research, 2014
Background: Chronic obstructive pulmonary disease (COPD) is an inflammatory disorder marked by relative resistance to steroids. The IL-17 superfamily, which mediates cross-talk between the adaptive and innate immune systems, has been associated with diminished responses to steroids. Increasing evidence supports elevated IL-17 expression in the lung of COPD subjects. However, whether cells of the immune system (systemic) and/or local lung cells are contributing to the elevated IL-17 remains unclear. To address this issue, we utilized a human parenchymal lung tissue explant culture system with cigarette smoke exposure to investigate the expression of IL-17 and the mechanisms involved. Methods: Parenchymal lung tissue removed from 10 non-COPD and 8 COPD patients was sectioned and cultured with different concentrations of cigarette smoke extract (CSE) for 3 or 6 hours. Tissue viability was evaluated by LDH (lactate dehydrogenase) in culture supernatants. Western blot and real-time PCR were performed to evaluate IL-17A/F expression. To investigate the mechanisms, pharmacological inhibitors for MAPK p38, ERK1/2, NF-κB and PI3K pathways were added into the culture media.
Expression of the T Helper 17-Associated Cytokines IL-17A and IL-17F in Asthma and COPD
CHEST Journal, 2010
A sthma and COPD are common conditions that account for substantial morbidity and mortality worldwide. Asthma affects 5% to 10% of adults, of whom 10% have severe disease. 1,2 Severe asthma represents a disproportionate health-care burden as it leads to debilitating chronic symptoms despite optimal standard asthma treatment and contributes to more than half of the health-care costs attributed to asthma. 1-4 COPD is predicted to be the third leading cause of death in 2030. 5,6 Both conditions are characterized by airfl ow obstruction with airway infl ammation and remodeling. COPD is considered a neutrophilic airway disease with increased infi ltration of the airway with CD8 1 T cells, 7 whereas asthma is characterized by Th2 cytokine expression and eosinophilic infl ammation. 8 However, there is increasing recognition that asthma and COPD are diseases with phenotypic heterogeneity in terms of clinical expression, airway dysfunction, and immunopathology. 9,10 Indeed, the Background: Asthma and COPD are characterized by airway dysfunction and infl ammation. Neutrophilic airway infl ammation is a common feature of COPD and is recognized in asthma, particularly in severe disease. The T helper (Th) 17 cytokines IL-17A and IL-17F have been implicated in the development of neutrophilic airway infl ammation, but their expression in asthma and COPD is uncertain. Methods: We assessed IL-17A and IL-17F expression in the bronchial submucosa from 30 subjects with asthma, 10 ex-smokers with mild to moderate COPD, and 27 nonsmoking and 14 smoking control subjects. Sputum IL-17 concentration was measured in 165 subjects with asthma and 27 with COPD. Results: The median (interquartile range) IL-17A cells/mm 2 submucosa was increased in mild to moderate asthma (2.1 [2.4]) compared with healthy control subjects (0.4 [2.8]) but not in severe asthma (P 5 .04). In COPD, IL-17A 1 cells/mm 2 submucosa were increased (0.5 [3.7]) compared with nonsmoking control subjects (0 [0]) but not compared with smoking control subjects (P 5 .046). IL-17F 1 cells/mm 2 submucosa were increased in severe asthma (2.7 [3.6]) and mild to moderate asthma (1.6 [1.0]) compared with healthy controls subjects (0.7 [1.4]) (P 5 .001) but was not increased in subjects with COPD. IL-17A and IL-17F were not associated with increased neutrophilic infl ammation, but IL-17F was correlated with the submucosal eosinophil count (r s 5 0.5, P 5 .005). The sputum IL-17 concentration in COPD was increased compared with asthma (2 [0-7] pg/mL vs 0 [0-2] pg/mL, P , .0001) and was correlated with post-bronchodilator FEV 1 % predicted (r 5 2 0.5, P 5 .008) and FEV 1 /FVC (r 5 2 0.4, P 5 .04). Conclusions: Our fi ndings support a potential role for the Th17 cytokines IL-17A and IL-17F in asthma and COPD, but do not demonstrate a relationship with neutrophilic infl ammation.
Modulation of bronchial epithelial cells by IL-17
Journal of Allergy and Clinical Immunology, 2001
Background: The induction of epithelial cytokines/chemokines is crucial in the migration of leukocytes, and its regulatory mechanisms remain incompletely defined. Objective: To determine the role of IL-17, a CD4 + T cell-derived cytokine, in modulation of primary bronchial epithelial cells, the expression of IL-6, IL-8, and intercellular adhesion molecule 1 (ICAM-1) and the potential involvement of mitogen-activated protein (MAP) kinases in IL-17-mediated signaling were examined. Methods: The levels of gene expression and protein production for IL-6 and IL-8 in IL-17-treated cells, in the presence or absence of MAP kinase inhibitors, were analyzed by RT-PCR and ELISA, respectively, and activation of MAP kinases was determined by Western blot analyses. Results: We showed first that IL-17 induced time-dependent expression of IL-6 and IL-8 but not of the chemokines eotaxin and RANTES. In addition, IL-17 induced activation of extracellular signal-regulated kinase 1/2 but not of p38 or JNK kinases. A selective MAP kinase kinase inhibitor, PD98059, inhibited IL-17-induced IL-6 and IL-8. A combination of IL-17 and each of the cytokines IL-4, IL-13, and IFN-γ further enhanced IL-8 expression. IL-17 alone did not induce ICAM-1 expression and showed no effect on IL-4-or IL-13-induced ICAM-1 expression. In contrast, a combination of IL-17 and IFN-γ augmented IL-6 and ICAM-1 expression. Conclusion: These findings suggest that IL-17, alone or in combination with other cytokines, modulates airway inflammation via-in part-the expression of epithelial IL-6, IL-8, and ICAM-1. (
Increased Sputum IL-17A Level in Non-asthmatic Eosinophilic Bronchitis
Lung, 2018
Background Non-asthmatic eosinophilic bronchitis (NAEB) is one common cause of chronic cough which is characterized as airway eosinophilic inflammation like asthma but lack of airway hyper-responsiveness. Previous studies showed that Th2-pathway plays a role in NAEB, but the role of non-Th2 pathway in mechanism of NAEB remains unknown. Recently, IL-17A, a Th17-pathway cytokine, has been demonstrated to be involved in asthma development. However, the relationship between Th17-pathway and NAEB is unknown. Methods We aim to assess the airway level of IL-17A in the subjects with NAEB. Relationships between the IL-17A level and airway function in NAEB or asthma are also observed. We measured IL-17A concentrations in the sputum supernatant from 12 subjects with EB, 16 subjects with asthma [9 eosinophilic asthmatic (EA) and 7 non-eosinophilic asthmatic (NEA) according to the sputum eosinophil ≥ 3%], and 9 healthy control subjects. Results Increasing IL-17A level was found in NAEB group (29.65 ± 8.13 pg/ml), EA group (32.45 ± 3.22 pg/ml), and NEA group (29.62 ± 6.91 pg/ml) compared with the healthy control group (17.05 ± 10.30 pg/ml) (P < 0.05, P < 0.01, P < 0.05, respectively). The sputum IL-17A level was correlated with FENO (r = 0.44, P < 0.01), FEV1/FVC% (r = − 0.38, P < 0.05), MMEF%pred (r = − 0.34, P < 0.05), and sputum neutrophil% (r = 0.33, P < 0.05) in total. Conclusion Th17-pathway may play a role not only in asthmatics, but also in subjects with NAEB, as reflected by increasing IL-17A concentrations in sputum supernatant.
Frontiers in immunology, 2017
Inflammation plays a central role in the development of asthma, which is considered an allergic disease with a classic Th2 inflammatory profile. However, cytokine IL-17 has been examined to better understand the pathophysiology of this disease. Severe asthmatic patients experience frequent exacerbations, leading to infection, and subsequently show altered levels of inflammation that are unlikely to be due to the Th2 immune response alone. This study estimates the effects of anti-IL-17 therapy in the pulmonary parenchyma in a murine asthma model exacerbated by LPS. BALB/c mice were sensitized with intraperitoneal ovalbumin and repeatedly exposed to inhalation with ovalbumin, followed by treatment with or without anti-IL-17. Twenty-four hours prior to the end of the 29-day experimental protocol, the two groups received LPS (0.1 mg/ml intratracheal OVA-LPS and OVA-LPS IL-17). We subsequently evaluated bronchoalveolar lavage fluid, performed a lung tissue morphometric analysis, and meas...
IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines
Journal of allergy and …, 2001
Background: IL-17 is a cytokine that has been reported to be produced by T lymphocytes. In vitro, IL-17 activates fibroblasts and macrophages for the secretion of GM-CSF, TNF-α, IL-1β, and IL-6. A number of these cytokines are involved in the airway remodeling that is observed within the lungs of asthmatic individuals. Objective: In this study, we investigated the expression of IL-17 in sputum and bronchoalveolar lavage specimens obtained from asthmatic subjects and from nonasthmatic control subjects. Methods: IL-17 was detected through use of immunocytochemistry, in situ hybridization, and Western blot. Bronchial fibroblasts were stimulated with IL-17, and cytokine production and chemokine production were detected through use of ELISA and RT-PCR. Results: Using immunocytochemistry, we demonstrated that the numbers of cells positive for IL-17 are significantly increased in sputum and bronchoalveolar lavage fluids of subjects with asthma in comparison with control subjects (P < .001 and P < .005, respectively). We demonstrated that in addition to T cells, eosinophils in sputum and bronchoalveolar lavage fluids expressed IL-17. Peripheral blood eosinophils were also positive for IL-17, and the level of IL-17 in eosinophils purified from peripheral blood was significantly higher in subjects with asthma than in controls (P < .01). To further investigate the mechanism of action of IL-17 in vivo, we examined the effect of this cytokine on fibroblasts isolated from bronchial biopsies of asthmatic and nonasthmatic subjects. IL-17 did enhance the production of profibrotic cytokines (IL-6 and IL-11) by fibroblasts, and this was inhibited by dexamethasone. Similarly, IL-17 increased the level of other fibroblast-derived inflammatory mediators, such as the α-chemokines, IL-8, and growth-related oncogene-α. Conclusion: Our results, which demonstrate for the first time that eosinophils are a potential source of IL-17 within asth-matic airways, suggest that IL-17 might have the potential to amplify inflammatory responses through the release of proinflammatory mediators such as α-chemokines. (J Allergy Clin Immunol 2001;108:430-8.)