Differential Regulation by Glucocorticoid of Interleukin-13–induced Eosinophilia, Hyperresponsiveness, and Goblet Cell Hyperplasia in Mouse Airways

Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 02/2003; 167(1):50-6. DOI: 10.1164/rccm.2110084
Source: PubMed


Interleukin (IL)-13 induces important features of bronchial asthma such as eosinophilic infiltration, airway hyperresponsiveness (AHR), and mucus hypersecretion. Although glucocorticoids suppress airway inflammation and remain the most effective therapy for asthma, the effects of glucocorticoids on the IL-13-dependent features are unknown. We studied the effects of dexamethasone on eotaxin production, eosinophil accumulation, goblet cell hyperplasia, and AHR after IL-13 administration into the airways of mice in vivo. MUC5AC gene expression, a marker of goblet cell hyperplasia, was also analyzed. IL-13 alone dose dependently induced AHR. Treatment with dexamethasone inhibited eotaxin expression and completely abolished eosinophil accumulation, but it did not affect AHR, MUC5AC overexpression, or goblet cell hyperplasia induced by IL-13. The effects of tumor necrosis factor-alpha on IL-13-induced AHR were also examined. Tumor necrosis factor-alpha did not affect AHR despite marked enhancement of eosinophil infiltration in IL-13-treated mice. These findings suggest that glucocorticoid is not sufficient to suppress IL-13-induced AHR or goblet cell hyperplasia and that eotaxin expression and eosinophilic inflammation do not have a causal relationship to the induction of AHR or goblet cell hyperplasia by IL-13. Control of steroid-resistant features induced by IL-13, including AHR and mucus production, may provide new therapeutic modalities for asthma.

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    • "Interestingly, the production of a thick mucus layer is one effective mechanism aimed to enhance epithelial barrier function and infers protection of these mucosal organs. It is commonly thought that these specific effects on intestinal epithelial cells are mediated by the Th2 cytokine IL-13 [20, 21], which is abundantly overexpressed after IL-33 stimulation/administration [8]; however, the possibility that IL-33 per se promotes epithelial differentiation towards a secretory type it may not be ruled out. In fact, IL-33 is also a potent inducer of Th2 cytokines that are pivotal in mounting potent immune responses against helminthes and fungi; in fact, early papers exploring IL-33 function have pointed out its fundamental role in eliminating intestinal parasites. "
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    ABSTRACT: Interleukin (IL)-33 is a recently identified cytokine belonging to the IL-1 family that is widely expressed throughout the body and has the ability to induce Th2 immune responses. In addition, IL-33 plays a key role in promoting host defenses against parasites through the expansion of a novel population of innate lymphoid cells. In recent years, a growing body of evidence has shown that the proinflammatory properties displayed by IL-33 are detrimental in several experimental models of inflammation; in others, however, IL-33 appears to have protective functions. In 2010, four different research groups consistently described the upregulation of IL-33 in patients with inflammatory bowel disease (IBD). Animal models of IBD were subsequently utilized in order to mechanistically determine the precise role of IL-33 in chronic intestinal inflammation, without, however, reaching conclusive evidence demonstrating whether IL-33 is pathogenic or protective. Indeed, data generated from these studies suggest that IL-33 may possess dichotomous functions, enhancing inflammatory responses on one hand and promoting epithelial integrity on the other. This review focuses on the available data regarding IL-33/ST2 in the physiological and inflammatory states of the gut in order to speculate on the possible roles of this novel IL-1 family member in intestinal inflammation.
    Mediators of Inflammation 05/2013; 2013(5):608187. DOI:10.1155/2013/608187 · 3.24 Impact Factor
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    • "Immediately after blood sampling, mice were exanguinated and their lungs were lavaged with 1 ml of physiological saline via a tracheal cannula. Cell counts were performed as previously described [6]. Samples were centrifuged at 2000 rpm for 10 min, and the supernatants were collected for cytokine ELISA. "
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    ABSTRACT: Background Clinical studies showed the contribution of viral infection to the development of asthma. Although mast cells have multiple roles in the pathogenesis of allergic asthma, their role of in the virus-associated pathogenesis of asthma remains unknown. Most respiratory viruses generate double-stranded (ds) RNA during their replication. dsRNA provokes innate immune responses. We recently showed that an administration of polyinocinic polycytidilic acid (poly IC), a mimetic of viral dsRNA, during allergen sensitization augments airway eosinophilia and hyperresponsiveness in mice via enhanced production of IL-13. Methods The effect of poly IC on allergen-induced airway eosinophilia was investigated for mast cell-conserved Kit+/+ mice and -deficient KitW/KitW-v mice. The outcome of mast cell reconstitution was further investigated. Results Airway eosinophilia and IL-13 production were augmented by poly IC in Kit+/+ mice but not in KitW/KitW-v mice. When KitW/KitW-v mice were reconstituted with bone marrow-derived mast cells (BMMCs), the augmentation was restored. The augmentation was not induced in the mice systemically deficient for TIR domain-containing adaptor-inducing IFN-β (TRIF) or interferon regulatory factor (IRF)-3, both mediate dsRNA-triggered innate immune responses. The augmentation was, however, restored in KitW/KitW-v mice reconstituted with TRIF-deficient or IRF-3-deficient BMMCs. Although leukotriene B4 and prostaglandin D2 are major lipid mediators released from activated mast cells, no their contribution was shown to the dsRNA-induced augmentation of airway eosinophilia. Conclusions We conclude that mast cells contribute to dsRNA-induced augmentation of allergic airway inflammation without requiring direct activation of mast cells with dsRNA or involvement of leukotriene B4 or prostaglandin D2.
    Respiratory research 03/2013; 14(1):28. DOI:10.1186/1465-9921-14-28 · 3.09 Impact Factor
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    • "Airway hyperresponsiveness (AHR) is one of the important traits that characterize bronchial asthma, apart from eosinophilic infiltration, reversible airway narrowing and chronic inflammation [1,2]. "
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    ABSTRACT: Airway hyperresponsiveness (AHR) is one of the important traits that characterize bronchial asthma. Goishi tea is a post-heating fermented tea that has been reported to have higher free radical scavenging activity. In this study, we evaluated the prophylactic effects of Goishi tea on AHR in BALB/c mice. The number of inflammatory cells in BAL fluid was considerably reduced in Goishi tea/Der f and Gallic acid/Der f groups as compared with Tap water/Der f group. Regarding inflammatory cells in BAL, a significant reduction of eosinophils and neutrophils was observed in Goishi tea-treated mice (p < 0.01), as well as in the Gallic acid/Der f group (p < 0.05), as compared with Tap water/Der f group. In asthmatic mice (Tap water/Der f group), the intensity of airway resistance increased simultaneously with the increase in acetylcholine concentration in a dose-dependant way. AHR was significantly inhibited in Goishi tea/Der f and Gallic acid/Der f (p < 0.01) groups as compared with the Tap water/Der f group. Regarding serum specific-IgG1, significantly lower levels of this antibody were observed in Goishi tea/Der f and Gallic acid/Der f groups as compared with the Tap water/Der f group (p < 0.05). In addition, adiponectin level was significantly higher in the Goishi tea group as compared with the Tap water treated mice (p < 0.01). The results suggest that Goishi tea consumption exerted an inhibitory effect on eosinophilic and neutrophilic infiltration in the lung, attenuated the increase in airway resistance and increased the production of adiponectin; thus reducing Der f induced allergic inflammatory process in mice.
    BMC Immunology 08/2011; 12:45. DOI:10.1186/1471-2172-12-45 · 2.48 Impact Factor
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