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Regulatory effects of IL-15 on allergen-induced airway obstruction.

ABSTRACT: BACKGROUND:Airway obstruction is a physiologic feature of asthma, and IL-15 might have an important role in asthma pathogenesis. OBJECTIVE:We tested the hypothesis that regulation of IL-15 is critical for preservation of allergen-induced airway hyperresponsiveness (AHR), airway resistance, and compliance in response to methacholine. METHODS:Airway inflammation, AHR, resistance, and compliance were assessed in Il15 gene-deficient mice and IL-15-overexpressing mice in an allergen-induced murine model of asthma. We assessed eosinophil numbers by using anti-major basic protein immunostaining, goblet cell hyperplasia by using periodic acid-Schiff staining, and cytokine and chemokine levels by performing quantitative PCR and ELISA. RESULTS:We made a novel observation that IL-15 deficiency promotes baseline airway resistance in naive mice. Moreover, rIL-15 delivery to the lung downregulates expression of proinflammatory cytokines and improves allergen-induced AHR, airway resistance, and compliance. These observations were further validated in doxycycline-inducible CC10-IL-15 bitransgenic mice. Doxycycline-exposed, Aspergillus species extract-challenged CC10-IL-15 bitransgenic mice exhibited significantly reduced levels of proinflammatory cytokines (IL-4, IL-5, and IL-13) and decreased goblet cell hyperplasia. Airway obstruction, including AHR and airway resistance, was diminished in allergen-challenged doxycycline-exposed compared with non-doxycycline-exposed CC10-IL-15 bitransgenic mice. Mechanistically, we observed that IL-15-mediated protection of airway obstruction is associated with induced IFN-?- and IL-10-producing regulatory CD4+CD25+ forkhead box p3 (Foxp3)+ T cells. Additionally, we found that a human IL-15 agonist (ALT-803) improved airway resistance and compliance in an experimental asthma model. CONCLUSION:We report our novel finding that IL-15 has a potent inhibitory effect on the airway obstruction that occurs in response to environmental allergens.

SUBMITTER: Venkateshaiah SU

PROVIDER: S-EPMC5723242 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Regulatory effects of IL-15 on allergen-induced airway obstruction.

Venkateshaiah Sathisha Upparahalli SU Zhu Xiang X Rajavelu Priya P Niranjan Rituraj R Manohar Murli M Verma Alok K AK Lasky Joseph A JA Mishra Anil A

The Journal of allergy and clinical immunology 20170609 3

<h4>Background</h4>Airway obstruction is a physiologic feature of asthma, and IL-15 might have an important role in asthma pathogenesis.<h4>Objective</h4>We tested the hypothesis that regulation of IL-15 is critical for preservation of allergen-induced airway hyperresponsiveness (AHR), airway resistance, and compliance in response to methacholine.<h4>Methods</h4>Airway inflammation, AHR, resistance, and compliance were assessed in Il15 gene-deficient mice and IL-15-overexpressing mice in an alle ...[more]

PMID: 28606589

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Project description:Interleukin-15 is a pleiotropic cytokine that is critical for the development and survival of multiple haematopoietic lineages. Mice lacking IL-15 have selective defects in populations of several pro-allergic immune cells including natural killer (NK) cells, NKT cells, and memory CD8+ T cells. We therefore hypothesized that IL-15-/- mice will have reduced inflammatory responses during the development of allergic airway disease (AAD).To determine whether IL-15-/- mice have attenuated allergic responses in a mouse model of AAD.C57BL/6 wild-type (WT) and IL-15-/- mice were sensitized and challenged with ovalbumin (OVA), and the development of AAD was ascertained by examining changes in airway inflammatory responses, Th2 responses, and lung histopathology.Here, we report that IL-15-/- mice developed enhanced allergic responses in an OVA-induced model of AAD. In the absence of IL-15, OVA-challenged mice exhibited enhanced bronchial eosinophilic inflammation, elevated IL-13 production, and severe lung histopathology in comparison with WT mice. In addition, increased numbers of CD4+ T and B cells in the spleens and bronchoalveolar lavage (BAL) were also observed. Examination of OVA-challenged IL-15R?-/- animals revealed a similar phenotype resulting in enhanced airway eosinophilia compared to WT mice. Adoptive transfer of splenic CD8+ T cells from OVA-sensitized WT mice suppressed the enhancement of eosinophilia in IL-15-/- animals to levels observed in WT mice, but had no further effects.These data demonstrate that mice with an endogenous IL-15 deficiency are susceptible to the development of severe, enhanced Th2-mediated AAD, which can be regulated by CD8+ T cells. Furthermore, the development of disease as well as allergen-specific Th2 responses occurs despite deficiencies in several IL-15-dependent cell types including NK, NKT, and ?? T cells, suggesting that these cells or their subsets are dispensable for the induction of AAD in IL-15-deficient mice.

Project description:BackgroundPreclinical studies implicate interleukin (IL)-1β as a key mediator of asthma and have shown the efficacy of IL-1 antagonism for treatment of allergic airway inflammation; human studies in this area are lacking.ObjectivesOur aim was to study the relationship of airway IL-1β to features of acute allergen-induced asthma exacerbation in humans.MethodsDust mite-allergic adults with mild asthma underwent inhalation challenge with Dermatophagoides farinae. Fractional exhaled nitric oxide (FeNO), induced sputum and peripheral blood samples were obtained pre- and 24 h post-challenge. Spirometry was performed before and throughout the challenge at 10-min intervals, and allergen responsiveness was defined by a 20% fall in Forced Expiratory Volume in 1 s (FEV1). Sputum samples were analyzed for inflammatory cells, cytokines and chemokines. Multiple linear regression was employed to test the association between sputum IL-1β concentration and biomarkers of T helper type 2 (T2)-dominant inflammation.ResultsFourteen volunteers underwent inhaled allergen challenge. Allergen responsive volunteers showed a greater positive change in IL-1β in sputum following allergen challenge compared to non-responders. Higher pre-challenge sputum IL-1β was associated with greater increase in sputum IL-5 (p = 0.004), sputum eosinophils (p = 0.001) and blood IL-5 (p = 0.003) following allergen challenge. Allergen-induced sputum IL-1β production was significantly associated with sputum and blood IL-5 (p < 0.001 and p = 0.007, respectively), sputum IL-4 (p = 0.001), IL-13 (p = 0.026), eosinophils (p = 0.008) and FeNO (p = 0.03).ConclusionsThe positive association between production of IL-1β and biomarkers of T2 inflammation, particularly IL-5, in humans is consistent with work in animal models that demonstrates a link between IL-1β and the pathophysiology of allergic asthma. The role of IL-1β in human asthma warrants further study.

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Regulatory effects of IL-15 on allergen-induced airway obstruction.

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Regulatory effects of IL-15 on allergen-induced airway obstruction.

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