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One mechanism of glucocorticoid action in asthma may involve the inhibition of IL-25 expression.

ABSTRACT: While the mechanism of action of classic cytokines in asthma has received increased attention from researchers, certain non-classical cytokines, such as IL-25, also participate in this mechanism. The present study was performed to investigate the changes in IL-25 (IL-17E) mRNA and protein in bronchial asthma and to further characterize the mechanism underlying the action of glucocorticoids in asthma. A total of 96 specific pathogen-free BALB/c male mice were randomly divided into three normal groups (after the first allergization, after the second allergization and after excitation), three asthma groups (with the same three subgroups), a dexamethasone group and a budesonide group (n=12/group). An asthma model was established via the ovalbumin-sensitized excitation method. Mice in the dexamethasone group received intraperitoneal injections of dexamethasone 1 h prior to each excitation, the budesonide group received a budesonide suspension via inhalation 2 h before and after each provocation, and the normal group was sensitized and challenged with isotonic saline. IL-25 protein expression levels in the bronchoalveolar lavage fluid were measured by ELISA, and the relative IL-25 mRNA content in lung tissue was determined by reverse transcription-quantitative polymerase chain reaction. Compared with the normal groups, both the protein and mRNA levels of IL-25 were significantly increased (P<0.05) in the asthma groups. Dexamethasone and budesonide groups exhibited significant protein and mRNA reductions in IL-25, as compared with the asthma group after excitation (P<0.05), whereas these two groups significantly increased levels compared with the normal group after excitation (P<0.05). No significant differences in IL-25 mRNA expression levels were detected in the dexamethasone and budesonide groups when compared with the normal group after excitation. Therefore, we conclude that IL-25 is involved throughout the process of inflammation and inflammatory immune pathogenesis in asthma. One of the mechanisms of glucocorticoid action in asthma may involve inhibition of IL-25 expression.

SUBMITTER: Lu W

PROVIDER: S-EPMC5348697 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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One mechanism of glucocorticoid action in asthma may involve the inhibition of IL-25 expression.

Lu Wei W Lu Chao C Zhang Chengming C Zhang Chenghao C

Experimental and therapeutic medicine 20161227 2

While the mechanism of action of classic cytokines in asthma has received increased attention from researchers, certain non-classical cytokines, such as IL-25, also participate in this mechanism. The present study was performed to investigate the changes in IL-25 (IL-17E) mRNA and protein in bronchial asthma and to further characterize the mechanism underlying the action of glucocorticoids in asthma. A total of 96 specific pathogen-free BALB/c male mice were randomly divided into three normal gr ...[more]

PMID: 28352347

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Project description:BackgroundSevere asthma is associated with substantial mortality and has unmet therapeutic need. A subset of severe asthma is characterized by neutrophilic airway inflammation. Classically activated (or M1) macrophages which express IL-12 and IL-23 are associated with airway neutrophilia in asthma. Exogenous IL-25 was reported to suppress intestinal inflammation in animal models of inflammatory bowel diseases via suppressing IL-12 and IL-23 production. We hypothesize that IL-25 ameliorates airway neutrophilia via inhibiting macrophage M1 polarization and the expression of IL-12 and IL-23 in asthma.MethodsIn a mouse model of neutrophil-dominant allergic airway inflammation, the effect of mouse recombinant IL-25 on airway inflammation were assessed by H&E staining and bronchoalveolar lavage (BAL) cell counting. The percentage of M1 macrophages in lung tissue and BAL cells were analyzed by flow cytometry. Quantitative PCR and immunostaining were performed to measure the expression of Il12, Il23, and inflammatory cytokines. Mechanistic experiments were performed in primary culture of macrophages from mouse lungs. The expression of IL-12, IL-23 and IL-25 in sputum was analyzed in a cohort of severe asthma and subjects with eosinophilic or non-eosinophilic asthma.ResultsIntranasal administration of IL-25 markedly decreased the number of neutrophils in BAL cells in a murine model of neutrophil-dominant allergic airway inflammation. Moreover, exogenous IL-25 decreased the number of M1 macrophages, and reduced the expression of IL-12, IL-23 in the lungs of the mouse model. Exogenous IL-25 also inhibited the expression of inflammatory cytokines IL-1β, IFN-γ, TNF-α and IL-17 A. In vitro, IL-25 suppressed IL-12 and IL-23 expression in lipopolysaccharide (LPS)-stimulated primary culture of mouse pulmonary macrophages. Mechanistically, IL-25 inhibited LPS-induced c-Rel translocation to nucleus via STAT3-dependent signaling. In a cohort of severe asthma, IL-25 protein levels in sputum were significantly lower than control subjects. The transcript levels of IL-12 and IL-23 were increased whereas IL-25 transcripts were decreased in sputum cells from subjects with non-eosinophilic asthma compared to eosinophilic asthma.ConclusionsIL-25 expression is downregulated in subjects with severe or non-eosinophilic asthma. Exogenous IL-25 ameliorates airway neutrophilia, at least in part, via inhibiting macrophage M1 polarization and the expression of IL-12 and IL-23.

Project description:RationaleCross-talk between glucocorticoid receptors and histone deacetylases (HDACs) under steroid-insensitive conditions has not been explored.ObjectivesTo evaluate expression and interaction of HDACs with glucocorticoid receptor isoforms in bronchoalveolar lavage and peripheral blood mononuclear cells from steroid-resistant versus steroid-sensitive patients with asthma.MethodsExpression of HDACs 1 through 11 was measured by real-time polymerase chain reaction in primary cells and in the DO11.10 cell line, designed to overexpress glucocorticoid receptor β. Glucocorticoid receptor β expression was inhibited in bronchoalveolar lavage cells by small interfering RNA. Human HDAC2 promoter fragments were cloned into a luciferase reporter vector, and transiently transfected with glucocorticoid receptor α- and β-encoding plasmids into the cells. Luciferase activity was then assayed in response to glucocorticoids.Measurements and main resultsLevels of HDAC2 mRNA, but not other histone deacetylases, were significantly decreased in bronchoalveolar lavage cells but not in peripheral blood mononuclear cells from steroid-resistant patients with asthma. Overexpression of glucocorticoid receptor β in DO11.10 cells selectively reduced HDAC2 mRNA and protein levels. Silencing of glucocorticoid receptor β in bronchoalveolar lavage cells from patients with asthma significantly increased HDAC2 mRNA. Luciferase activity assays with HDAC2 promoter reporter constructs identified two glucocorticoid-inducible regions in the HDAC2 promoter. Promoter activity was increased more than fourfold in dexamethasone-treated cells cotransfected with glucocorticoid receptor α. Cotransfection of glucocorticoid receptor β abolished this effect in a dose-dependent manner.ConclusionsGlucocorticoid receptor β controls expression of histone deacetylase 2 by inhibiting glucocorticoid response elements in its promoter. This highlights a novel mechanism by which glucocorticoid receptor β promotes steroid insensitivity (Li et al.: J Allergy Clin Immunol 2009;123:S146; and Li et al.: J Allergy Clin Immunol 2010;125:AB104).

Project description:BackgroundIL-17 is a modulator of the inflammatory response and is implicated in lung remodeling in both asthma and chronic obstructive pulmonary disease (COPD). Well as and probably in patients with asthma-COPD overlap (ACO).MethodsIn this study, we evaluated the response of the airways and alveolar septa to anti-IL-17 treatment in an ACO model. Fifty-six male BALB/c mice were sensitized with ovalbumin (OVA group), received porcine pancreatic elastase (PPE group), or both (ACO group). Mice were then treated with either anti-IL-17 monoclonal antibody or saline. We evaluated hyperresponsiveness, bronchoalveolar lavage fluid (BALF) cell counts, and mean alveolar diameter. We quantified inflammatory, response, extracellular matrix remodeling, oxidative stress markers, and signaling pathway markers.ResultsAnti-IL-17 treatment in the ACO anti-IL-17 group reduced the maximum response of respiratory system Rrs, Ers, Raw, Gtis, this when compared to the ACO group (p<0.05). There was a reduction in the total number of inflammatory cells, neutrophils, and macrophages in the BALF in the ACO anti-IL-17 group compared to the ACO group (p<0.05). There was attenuated dendritic cells, CD4+, CD8+, FOXP3, IL-1β, IL-2, IL-6, IL-13, IL-17, IL-33 in ACO anti-IL-17 group in airway and alveolar septum compared to the ACO group (p<0.05). We observed a reduction of MMP-9, MMP-12, TIMP-1, TGF-β, collagen type I in ACO anti-IL-17 group in airway and alveolar septum compared to the ACO group (p < 0.05). We also observed a reduction of iNOS and 8-iso-PGF2α in the airways and in the alveolar septum was reduced in the ACO anti-IL-17group compared to the ACO group (p < 0.05). Regarding the signaling pathways, NF-kB, ROCK-1, and ROCK-2 in the airway and alveolar septum were attenuated in the ACO anti-IL-17 group when compared to the ACO group (p<0.05).ConclusionsOur results suggest that inhibiting IL-17 modulates cell-associated cytokine production in lung tissue, extracellular matrix remodeling, and oxidative stress in ACO through the modulation of NF-kB and FOXP3.

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One mechanism of glucocorticoid action in asthma may involve the inhibition of IL-25 expression.

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One mechanism of glucocorticoid action in asthma may involve the inhibition of IL-25 expression.

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