Original Articles: Mechanisms of Allergy
IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines,☆☆

https://doi.org/10.1067/mai.2001.117929Get rights and content

Abstract

Background: IL-17 is a cytokine that has been reported to be produced by T lymphocytes. In vitro, IL-17 activates fibro-blasts 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 pro-fibrotic 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 asthmatic 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.)

Section snippets

Subjects

Eleven asthmatic subjects fulfilling the American Thoracic Society criteria for asthma17 were recruited (Table I). Of these, 6 patients agreed to undergo BAL and sputum induction. Sputum induction was done first; BAL was done 1 week later. The symptoms of these patients were controlled by regular use of inhaled selective β2-agonists only. Six of the patients with mild asthma were atopic, inasmuch as they had positive skin reactions to at least 1 common allergen. All subjects were nonsmokers or

RT-PCR

Fibroblasts were seeded in 6-well plates, grown to confluence, and stimulated with recombinant human IL-17 (rhIL-17; 25 ng/mL) in the presence or absence of dexamethasone (Dex; 10–7 mol/L) for 24 hours. Optimal concentrations of Dex and IL-17 were selected according to a preliminary concentration-response curve. Cell viability was not affected by Dex as assessed by the Trypan blue exclusion method. Dex was used in co-incubation with rhIL-17 in culture medium on bronchial fibroblasts. Controls

Expression of IL-17 immunoreactivity in sputum and BAL fluid

Cells positive for IL-17 immunoreactivity were found in sputum and BAL fluid of both asthmatic and normal control subjects. The numbers of cells expressing IL-17 immunoreactive protein were significantly higher in sputum (P < .001) and BAL (P < .005) recovered from asthmatic subjects than in sputum and BAL recovered from nonasthmatic controls (Fig 1).

. A, Expression of IL-17-immunoreactivity in sputum from normal (solid circles ; n = 7) and asthmatic (open circles ; n = 6) subjects. B,

Discussion

In the present study, we demonstrated that IL-17 is upregulated in asthma, that eosinophils also are cellular sources of its production, and that IL-17 increases synthesis of IL-6 and IL-11 by bronchial fibroblasts derived from bronchial biopsies of asthmatic subjects.

Several reports have demonstrated that IL-17 has the capacity to induce the production of other cytokines from structural cells and to enhance the surface expression of intracellular adhesion molecule-1.4, 5 Chabaud et al15

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  • Cited by (0)

    Supported in part by Medical Research Council Canada (MT-13273), Astra Canada, and the Chair de Pneumologie de la Fondation J. Bégin. S. Molet is the recipient of a Canadian Lung Association/Canadian Thoracic Society and Merck-Frosst fellowship. Q. Hamid and J. Chakir are the recipients of a Chercheur-Boursier award from the Fonds de la Recherche en Santé du Québec.

    ☆☆

    Reprint requests: Jamila Chakir, PhD, Centre de Recherche, Hôpital Laval, 2725 Chemin Sainte-Foy, Sainte-Foy (QC), G1V 4G5 Canada.

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