Th17 cytokines: novel potential therapeutic targets for COPD pathogenesis and exacerbations (original) (raw)
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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.
Clinical & Experimental Immunology, 2009
There are increased numbers of activated T lymphocytes in the bronchial mucosa of stable chronic obstructive pulmonary disease (COPD) patients. T helper type 17 (Th17) cells release interleukin (IL)-17 as their effector cytokine under the control of IL-22 and IL-23. Furthermore, Th17 numbers are increased in some chronic inflammatory conditions. To investigate the expression of interleukin (IL)-17A, IL-17F, IL-21, IL-22 and IL-23 and of retinoic orphan receptor RORC2, a marker of Th17 cells, in bronchial biopsies from patients with stable COPD of different severity compared with age-matched control subjects. The expression of IL-17A, IL-17F, IL-21, IL-22, IL-23 and RORC2 was measured in the bronchial mucosa using immunohistochemistry and/or quantitative polymerase chain reaction. The number of IL-22 + and IL-23 + immunoreactive cells is increased in the bronchial epithelium of stable COPD compared with control groups. In addition, the number of IL-17A + and IL-22 + immunoreactive cells is increased in the bronchial submucosa of stable COPD compared with control non-smokers. In all smokers, with and without disease, and in patients with COPD alone, the number of IL-22 + cells correlated significantly with the number of both CD4 + and CD8 + cells in the bronchial mucosa. RORC2 mRNA expression in the bronchial mucosa was not significantly different between smokers with normal lung function and COPD. Further, we report that endothelial cells express high levels of IL-17A and IL-22. Increased expression of the Th17-related cytokines IL-17A, IL-22 and IL-23 in COPD patients may reflect their involvement, and that of specific IL-17-producing cells, in driving the chronic inflammation seen in COPD.
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...
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.
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.
Regulation of IL-17 in chronic inflammation in the human lung
Clinical Science, 2011
The regulation of human Th17 cell effector function by Treg cells (regulatory T-cells) is poorly understood. In the present study, we report that human Treg (CD4+CD25+) cells inhibit the proliferative response of Th17 cells but not their capacity to secrete IL (interleukin)-17. However, they could inhibit proliferation and cytokine production by Th1 and Th2 cells as determined by IFN-γ (interferon-γ) and IL-5 biosynthesis. Currently, as there is interest in the role of IL-17-producing cells and Treg cells in chronic inflammatory diseases in humans, we investigated the presence of CD4+CD25+ T-cells and IL-17 in inflammation in the human lung. Transcripts for IL-17 were expressed in mononuclear cells and purified T-cells from lung tissue of patients with chronic pulmonary inflammation and, when activated, these cells secrete soluble protein. The T-cell-specific transcription factors RORCv2 (retinoic acid-related orphan receptor Cv2; for Th17) and FOXP3 (forkhead box P3; for Treg cells...
Contribution of IL-17 to the pulmonary inflammatory response
Th 17 Cells: Role in Inflammation and Autoimmune Disease, 2009
ABSTRACT Airway exposure to endotoxin and other microbial Toll-like receptor (TLR) agonists induces a rapid production of mediators including IL-1, neutrophil recruitment and bronchoconstriction, which are abrogated in mice deficient for distinct TLRs or the common adaptor molecule myeloid differentiation factor 88 (MyD88). Intranasal IL-17 administration causes acute neutrophilic lung inflammation in a proinflammatory environment. Recent investigations revealed that IL-17 is up-regulated upon endotoxin aerosol exposure and neutralization of IL-17 diminished endotoxininduced inflammation, suggesting a role of endogenous IL-17 in endotoxin-induced lung inflammation. Furthermore, administration of IL-1β mobilizes neutrophils and induces IL-17 production in the lung. Therefore, IL-17 might participates in IL-1β-induced lung inflammation. Importantly, lung injury leads to NALP3 inflammasome activation, leading to IL-1β-dependent acute inflammation. The participation of IL-17 in this response is discussed. In conclusion, TLR-agonist and injury-induced lung inflammation depend in part on IL-1β and IL-17. The role of inflammasome activation cleaving pro-IL-1β leading to mature IL-1ß and IL-1β-dependent IL-17 production and inflammation need to be explored further.
TH17-associated cytokines (IL-17A and IL-17F) in severe asthma
2009
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The IL-17 Family of Cytokines - Applications in Respiratory Medicine and Allergology
Recent Patents on Inflammation & Allergy Drug Discovery, 2008
The excessive accumulation of granulocytes is believed to constitute an important factor in inflammatory airway diseases, including asthma and chronic obstructive pulmonary disease (COPD). Notably, T helper (Th) cells are known to produce cytokines that are involved in the mobilization of eosinophils and neutrophils. Currently, it is believed that a third population of Th cells, the recently described Th17 population, accounts for the production of several members of the interleukin (IL)-17 family of cytokines. The members of this cytokine family have proven abilities to recruit and activate neutrophils and eosiniphils. This review summarizes the evidence that these cytokines constitute key mediators of the Th-controlled granulocyte influx in airway disease and points out molecular target candidates for therapy as well as related patents.