Is Interleukin-13 Critical in Maintaining Airway Hyperresposiveness in Allergen-challenged Mice? (original) (raw)
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Effects of IL-13 on airway responses in the guinea pig
American Journal of Physiology - Lung Cellular and Molecular Physiology, 2002
Levels of interleukin (IL)-13 are increased in asthmatic airways. IL-13 has been shown to be necessary and sufficient for allergen-induced airway hyperresponsiveness and increased inflammatory cell counts in bronchoalveolar lavage (BAL) fluid in a murine model of asthma but is thought to protect against airway inflammation when low doses are provided to the guinea pig lung. To determine the role of IL-13 in the guinea pig, we studied the effects of a 360-g/kg dose of nebulized IL-13 in naive animals and of IL-13 abrogation after airway challenge of sensitized animals. Nebulized IL-13 significantly decreased the dose of histamine required to double baseline respiratory system resistance (ED 100, 22 Ϯ 3 vs. 13 Ϯ 2 nmol/kg; P Ͻ 0.05) and was associated with recovery of significantly greater numbers of macrophages, lymphocytes, eosinophils, and neutrophils in BAL fluid. Guinea pigs pretreated with a fusion protein that binds IL-13 [soluble IL-13 receptor ␣2 (sIL-13R␣2)] were protected from developing antigen-induced airway hyperresponsiveness (ED100, 210 Ϯ 50 vs. 20 Ϯ 10 nmol/kg; P Ͻ0.01). sIL-13R␣2 (2 doses of 20 mg/kg) significantly reduced the histological grade of allergen-induced lung eosinophil accumulation, whereas the effects of two doses of 10 mg/kg were not significant. These findings demonstrate that the tissue levels of IL-13 induced by allergen challenge of sensitized animals induce airway hyperresponsiveness and inflammation and that IL-13 is required for the expression of allergen-induced airway hyperresponsiveness in the guinea pig ovalbumin model. interleukin-13; eosinophil; inflammation; airway hyperresponsiveness; ovalbumin
American Journal of Physiology-Lung Cellular and Molecular Physiology, 2005
IL-13 is a mediator of allergen-induced airway hyperresponsiveness (AHR). The aim of this study was to evaluate whether eotaxin and IL-5 were implicated in the effects of IL-13 on allergen-induced AHR or whether IL-13 may exert its effects through direct actions on airway smooth muscle (ASM). To study this question airway inflammation and AHR were induced in mice by sensitization and subsequent challenge on three successive days with ovalbumin. A monoclonal anti-IL-13 antibody administered before each challenge significantly reduced AHR without affecting airway eosinophilia. No changes of mRNA in BAL and lung tissues or protein levels in BAL of IL-5 or eotaxin were found following anti-IL-13 treatment. Combined injection of monoclonal anti-IL-5 and antieotaxin antibodies before each antigen challenge blocked airway eosinophilia but failed to reduce AHR. IL-13 induced calcium transients in cultured murine ASM cells and augmented the calcium and contractile responses of these cells to...
IL-13 receptor α2 contributes to development of experimental allergic asthma
Journal of Allergy and Clinical Immunology, 2013
Background-IL-13 receptor alpha2 (IL-13R 2) binds IL-13 with high affinity and modulates IL-13 responses. There are soluble and membrane forms of IL-13R 2 generated by alternative splicing in mice but humans express only the membrane form (memIL-13R 2). Objective-We determined the role of memIL-13R 2 in development of allergic inflammation in mouse models of asthma. Methods-IL-13R 2-deficient and memIL-13R 2 lung epithelium-specific transgenic mice were challenged with house dust mite (HDM). Airway hyperresponsiveness (AHR) and inflammation were assessed by airway pressure time index, bronchoalveolar lavage (BAL) cell counts and lung histology. The mucus production was determined by periodic acid-Schiff (PAS) staining of lung sections, western blot analysis of chloride channel calcium activated 3 (CLCA3) expression in lung homogenates, and ELISA of Muc5ac in BAL fluid (BALF). The expression of cytokines and chemokines was determined by RT-quantitative PCR. Results-In IL-13R 2-deficient mice, AHR and airway inflammation were attenuated compared to wild type mice following HDM challenge. Lung epithelium overexpression of memIL-13R 2 in the IL-13R 2-deficient mice reconstituted AHR and inflammation to levels similar to those observed in HDM-challenged wild type mice. Mucus production was attenuated in lungs from HDM-treated IL-13R 2-deficient mice while lung epithelium overexpression of memIL-13R 2 increased mucus production. Lung epithelium overexpression of memIL-13R 2 had no effect on
Clinical & Experimental Allergy, 2007
T-helper type 2 (Th2)-derived cytokines such as IL-4, IL-5, IL-9 and IL-13 play an important role in the synthesis of IgE and in the promotion of allergic eosinophilic inflammation and airway wall remodelling. We determined the importance of IL-13 alone, and of the four Th2 cytokines together, by studying mice in which either IL-13 alone or the Th2 cytokine cluster was genetically disrupted. The knock-out mice and their BALB/c wild-type (wt) counterparts were sensitized and repeatedly exposed to ovalbumin (OVA) aerosol. Bronchial responsiveness measured as the concentration of acetylcholine aerosol needed to increase baseline lung resistance by 100% (PC100) was decreased in IL-13-/-, but increased in IL-4/5/9/13-/- mice. Chronic allergen exposure resulted in airway hyperresponsiveness (AHR) in wt mice but not in both genetically modified mice. After allergen exposure, eosinophil counts in bronchoalveolar lavage fluid and in airways mucosa, and goblet cell numbers were not increased in IL-4/5/9/13-/- mice, and were only attenuated in IL-13-/- mice. Airway smooth muscle (ASM) hyperplasia after allergen exposure was prevented in both IL-13-/- and IL-4/5/9/13-/- mice to an equal extent. Similarly, the rise in total or OVA-specific serum IgE levels was totally inhibited. IL-13 is mainly responsible for AHR, ASM hyperplasia and increases in IgE, while IL-4, -5 and -9 may contribute to goblet cell hyperplasia and eosinophilic inflammation induced by chronic allergen exposure in a murine model. Both redundancy or complementariness of Th2 cytokines can occur in vivo, according to specific aspects of the allergic response.
Allergen-dependent solubilization of IL-13 receptor α2 reveals a novel mechanism to regulate allergy
Journal of Allergy and Clinical Immunology, 2007
Background: Allergic sensitization affects half of western populations and often precedes the development of allergic disorders including asthma. Despite the critical role of allergens in the pathogenesis of these disorders, little is known about how allergens modulate the immune response. IL-13 receptor a2 (IL-13Ra2) is a decoy receptor for IL-13. Objective: Although the existence of soluble IL-13Ra2 has been documented, the mechanisms underlying its generation are unknown. Many allergens possess protease activity; we investigated whether IL-13Ra2 is solubilized in response to allergen treatment. Methods: We evaluated the ability of allergens to solubilize IL-13Ra2 in vitro and in vivo and examined the effect on IL-13 signaling and responses. Results: We determined that treatment of cells with house dust mite (HDM) allergen or purified Dermatophagoides pteronyssinus or Dermatophagoides farinae, but not other allergens, resulted in release of soluble IL-13Ra2 that was biologically active and inhibited IL-13 signaling. Prolonged exposure to HDM or treatment with mold allergens resulted in IL-13Ra2 degradation. This was associated with increased IL-13 signaling. A single treatment of HDM in vivo resulted in release of IL-13Ra2 into the bronchoalveolar lavage (BAL) fluid. BAL fluid from humans also contained IL-13Ra2; BAL fluid from individuals with asthma contained less IL-13Ra2 than that from controls. Conclusion: Allergen exposure can directly affect the level of soluble IL-13Ra2 in a way that affects IL-13 signaling and responses. Clinical implications: Soluble IL-13Ra2 may be an important biomarker of environmental allergen exposure and asthma. (J Allergy Clin Immunol 2007;119:375-83.)
Resistance to antigen-induced airway hyperresponsiveness requires endogenous production of IL-12
Journal of immunology (Baltimore, Md. : 1950), 1998
We have demonstrated previously that susceptibility of murine strains to the development of allergic airway responses is associated with a type 2 cytokine pattern. In the present study, we examine the in vivo role of IL-12 in the immune response to allergen exposure in susceptible (A/J) and resistant (C3H/HeJ, C3H) strains of mice. OVA sensitization and challenge induced significant increases in airway reactivity in A/J mice as compared with their PBS-challenged controls, while no increases in airway reactivity were observed in OVA-challenged C3H mice. OVA exposure of A/J mice resulted in marked increases in the Th2 cytokines, IL-4 and IL-10, in the bronchoalveolar lavage fluid, whereas increases in IFN-gamma were observed in C3H mice. Strikingly, anti-IL-12 mAb (1 mg/mouse) treatment resulted in threefold increases in airway reactivity in OVA-challenged resistant C3H mice, concomitant with significant increases in bronchoalveolar lavage levels of Th2 cytokines and decreases in IFN-...