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      Expression of the T Helper 17-Associated Cytokines IL-17A and IL-17F in Asthma and COPD

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          Abstract

          Background:

          Asthma and COPD are characterized by airway dysfunction and inflammation. Neutrophilic airway inflammation 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 inflammation, 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 = .04). In COPD, IL-17A + 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 = .046). IL-17F + 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 = .001) but was not increased in subjects with COPD. IL-17A and IL-17F were not associated with increased neutrophilic inflammation, but IL-17F was correlated with the submucosal eosinophil count ( rs = 0.5, P = .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 = −0.5, P = .008) and FEV 1/FVC ( r = −0.4, P = .04).

          Conclusions:

          Our findings 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 inflammation.

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          Most cited references26

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          A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.

          Interleukin 17 (IL-17) has been linked to autoimmune diseases, although its regulation and function have remained unclear. Here we have evaluated in vitro and in vivo the requirements for the differentiation of naive CD4 T cells into effector T helper cells that produce IL-17. This process required the costimulatory molecules CD28 and ICOS but was independent of the cytokines and transcription factors required for T helper type 1 or type 2 differentiation. Furthermore, both IL-4 and interferon-gamma negatively regulated T helper cell production of IL-17 in the effector phase. In vivo, antibody to IL-17 inhibited chemokine expression in the brain during experimental autoimmune encephalomyelitis, whereas overexpression of IL-17 in lung epithelium caused chemokine production and leukocyte infiltration. Thus, IL-17 expression characterizes a unique T helper lineage that regulates tissue inflammation.
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            Chronic obstructive pulmonary disease.

            P Barnes (2000)
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              Regulation of inflammatory responses by IL-17F

              Although interleukin (IL) 17 has been extensively characterized, the function of IL-17F, which has an expression pattern regulated similarly to IL-17, is poorly understood. We show that like IL-17, IL-17F regulates proinflammatory gene expression in vitro, and this requires IL-17 receptor A, tumor necrosis factor receptor–associated factor 6, and Act1. In vivo, overexpression of IL-17F in lung epithelium led to infiltration of lymphocytes and macrophages and mucus hyperplasia, similar to observations made in IL-17 transgenic mice. To further understand the function of IL-17F, we generated and analyzed mice deficient in IL-17F or IL-17. IL-17, but not IL-17F, was required for the initiation of experimental autoimmune encephalomyelitis. Mice deficient in IL-17F, but not IL-17, had defective airway neutrophilia in response to allergen challenge. Moreover, in an asthma model, although IL-17 deficiency reduced T helper type 2 responses, IL-17F–deficient mice displayed enhanced type 2 cytokine production and eosinophil function. In addition, IL-17F deficiency resulted in reduced colitis caused by dextran sulfate sodium, whereas IL-17 knockout mice developed more severe disease. Our results thus demonstrate that IL-17F is an important regulator of inflammatory responses that seems to function differently than IL-17 in immune responses and diseases.
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                Author and article information

                Journal
                Chest
                chest
                chest
                Chest
                Chest
                American College of Chest Physicians
                0012-3692
                1931-3543
                November 2010
                10 June 2010
                10 June 2010
                : 138
                : 5
                : 1140-1147
                Affiliations
                [1]From the Institute of Lung Health (Ms Doe; Drs Bafadhel, Siddiqui, Desai, and Brightling; and Mr Mistry), Leicester; AstraZeneca Charnwood (Dr Rugman and Ms McCormick), Loughborough; and MedImmune Ltd (Drs Woods, May, Sleeman, and Anderson), Cambridge, England.
                Author notes
                Correspondence to: Christopher E. Brightling, PhD, FCCP, Institute for Lung Health, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Groby Rd, Leicester, LE3 9QP, England; e-mail: ceb17@ 123456le.ac.uk
                Article
                093058
                10.1378/chest.09-3058
                2972626
                20538817
                d6226b16-c65e-45d7-b84e-d9023322a2cf
                © 2010 American College of Chest Physicians

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial License ( http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Information for commercial entities is available online ( http://www.chestpubs.org/site/misc/reprints.xhtml).

                History
                : 21 December 2009
                : 12 May 2010
                Categories
                Original Research
                Asthma

                Respiratory medicine
                Respiratory medicine

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