Allergen-dependent solubilization of IL-13 receptor α2 reveals a novel mechanism to regulate allergy (original) (raw)
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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
Immunology, 1997
Interleukin-13 (IL-13) shares many, but not all, of the properties of the prototypic T-helper type 2 (Th2) cytokine IL-4, but its role in allergen-driven T-cell responses remains poorly defined. We hypothesized that allergen stimulation of peripheral blood T cells from patients with atopic disease compared with non-atopic controls results in elevated IL-13 synthesis in the context of a 'Th2-type' pattern. Freshly isolated peripheral blood mononuclear cells (PBMC) obtained from sensitized atopic patients with allergic disease, and non-atopic control subjects, were cultured with the allergens Phleum pratense (Timothy grass pollen) or Dermatophagoides pteronyssinus (house dust mite) and the non-allergenic recall antigen Mycobacterium tuberculosis purified protein derivative (PPD). Supernatant concentrations of IL-13, along with IL-5 and interferon-y (IFN-y) (Th2-and Thl-type cytokines, respectively) were determined by enzyme-linked immunosorbent assay (ELISA). Allergen-induced IL-13 and IL-5 production by T cells from patients with allergic disease was markedly elevated (P =00075 and P=0O0004, respectively) compared with non-atopic controls, whereas IFN-y production was not significantly different. In contrast to allergen, the prototypic Thl-type antigen M tuberculosis PPD induced an excess of IFN-y over IL-13 and IL-5 production, and absolute concentrations of cytokines were not affected by the presence or absence of atopic disease. Addition of exogenous recombinant IFN-y or IL-12, cytokines known to inhibit Th2-type responses, significantly inhibited allergen-driven production of both IL-13 and IL-5, but not T-cell proliferation, whereas exogenous IL-4 did not significantly affect production of IL-13 or IL-5. We conclude that allergen-specific T cells from atopic subjects secrete elevated quantities of IL-13 compared with non-atopic controls, in the context of a Th2-type pattern of cytokine production.
IL-13 Regulates the Immune Response to Inhaled Antigens
The Journal of Immunology, 2005
The large inhibitory effect of IL-13 blockers on the asthma phenotype prompted us to ask whether IL-13 would play a role in regulating the allergic immune response in addition to its documented effects on structural pulmonary cells. Because IL-13 does not interact with murine T or B cells, but with monocytes, macrophages, and dendritic cells (DCs), we examined the role of IL-13 in the activation of pulmonary macrophages and DCs and in the priming of an immune response to a harmless, inhaled Ag. We found that a majority of cells called “alveolar or interstitial macrophages” express CD11c at high levels (CD11chigh) and are a mixture of at least two cell types as follows: 1) cells of a mixed phenotype expressing DC and macrophage markers (CD11c, CD205, and F4/80) but little MHC class II (MHC II); and 2) DC-like cells expressing CD11c, CD205, MHC II, and costimulatory molecules. Endogenous IL-13 was necessary to induce and sustain the increase in MHC II and CD40 expression by pulmonary ...
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-4 and IL-13 signaling in allergic airway disease
Cytokine, 2015
Aberrant production of the prototypical type 2 cytokines, interleukin (IL)-4 and IL-13 has long been associated with the pathogenesis of allergic disorders. Despite tremendous scientific inquiry, the similarities in their structure, and receptor usage have made it difficult to ascertain the distinct role that these two look-alike cytokines play in the onset and perpetuation of allergic inflammation. However, recent discoveries of differences in receptor distribution, utilization/ assembly and affinity between IL-4 and IL-13, along with the discovery of unique innate lymphoid 2 cells (ILC2) which preferentially produce IL-13, not IL-4, are beginning to shed light on these mysteries. The purpose of this chapter is to review our current understanding of the distinct roles that IL-4 and IL-13 play in allergic inflammatory states and the utility of their modulation as potential therapeutic strategies for the treatment of allergic disorders.
Interleukin 13 receptors as biochemical markers in atopic patients
Journal of investigational allergology & clinical immunology, 2011
Interleukin (IL) 13, a type 2 helper T cell (T(H)2), is an important regulator of inflammatory immune responses. It mediates its action through a receptor complex consisting of IL-13Ralpha1 and IL-4Ralpha. IL-13Ralpha2 binds IL-13 with high affinity and is thought to act primarily as a decoy receptor, sequestering IL-13 and thus inhibiting its action. Our aim was to clarify the role of these receptors in the diagnosis and follow-up of atopic patients. We genotyped the 1398A>G polymorphism in the IL-13Ralpha1 gene using restriction fragment length polymorphism for causal genetic diversity and measured serum levels of IL-13Ralpha2 in 105 atopic patients suffering from atopic asthma, atopic dermatitis, and atopic rhinitis (35 each). We compared the results with those of 35 nonatopic control individuals. Total immunoglobulin (Ig) E and serum IL-13Ralpha2 were measured using enzyme-linked immunosorbent assay, and the eosinophil counts were recorded. A significant increase in serum IL-...
Genetic variants of IL-13 signalling and human asthma and atopy
Human Molecular Genetics, 2000
Asthma and atopy show epidemiological association and are biologically linked by T-helper type 2 (T h 2) cytokine-driven inflammatory mechanisms. IL-4 operates through the IL-4 receptor (IL-4R, a heterodimer of IL-4Rα and either γc or IL-13Rα1) and IL-13 operates through IL-13R (a heterodimer of IL-4Rα and IL-13Rα1) to promote IgE synthesis and IgE-based mucosal inflammation which typify atopy. Recent animal model data suggest that IL-13 is a central cytokine in promoting asthma, through the stimulation of bronchial epithelial mucus secretion and smooth muscle hyper-reactivity. We investigated the role of common genetic variants of IL-13 and IL-13Rα1 in human asthma, considering IgE levels. A novel variant of human IL-13, Gln110Arg, on chromosome 5q31, associated with asthma rather than IgE levels in casecontrol populations from Britain and Japan [peak odds ratio (OR) = 2.31, 95% CI 1.33-4.00]; the variant also predicted asthma and higher serum IL-13 levels in a general, Japanese paediatric population. Immunohistochemistry demonstrated that both subunits of IL-13R are prominently expressed in bronchial epithelium and smooth muscle from asthmatic subjects. Detailed molecular modelling analyses indicate that residue 110 of IL-13, the site of the charge-modifying variants Arg and Gln, is important in the internal constitution of the ligand and crucial in ligand-receptor interaction. A non-coding variant of IL-13Rα1, A1398G, on chromosome Xq13, associated primarily with high IgE levels (OR = 3.38 in males, 1.10 in females) rather than asthma. Thus, certain variants of IL-13 signalling are likely to be important promoters of human asthma; detailed functional analysis of their actions is needed.