Eotaxin-2 and eotaxin-3 expression is associated with persistent eosinophilic bronchial inflammation in patients with asthma after allergen challenge

Leiden University, Leyden, South Holland, Netherlands
Journal of Allergy and Clinical Immunology (Impact Factor: 11.48). 05/2005; 115(4):779-85. DOI: 10.1016/j.jaci.2004.11.045
Source: PubMed


Eotaxin-1, eotaxin-2, and eotaxin-3 are chemokines involved in the activation and recruitment of eosinophils through activation of their main receptor, CC chemokine receptor 3. The differential roles of these chemokines still remain to be established. It has been suggested that eotaxin-1 is an important mediator in the early phase of allergen-induced recruitment of eosinophils into the airways. Eotaxin-2 and eotaxin-3 might play a role in the subsequent persistence of allergen-induced bronchial eosinophilia.
The aim of this study was to determine the expression of eotaxins and eosinophil counts in the bronchial mucosa of subjects with mild asthma after resolution of the late-phase asthmatic response (LAR).
The expression of eotaxins and eosinophil counts were determined in bronchial biopsy specimens obtained from 10 subjects with mild asthma 48 hours after diluent and allergen challenge by using immunohistochemistry. Positively stained cells were counted in a 125-mum-deep zone of the lamina propria.
Eotaxin-2 and eotaxin-3 expression in bronchial mucosa was significantly increased 48 hours after allergen challenge ( P = .001 and P = .013, respectively). At this time point, when marked tissue eosinophilia was still present, these increases were positively correlated with the magnitude of the LAR ( r = 0.72, P = .019 and r = 0.64, P = .046, respectively). Furthermore, eotaxin-2 expression was associated with the number of eosinophils after allergen challenge ( r = 0.72, P = .018).
Our findings suggest that eotaxin-2 and eotaxin-3 might account for the persistence of bronchial eosinophilia after resolution of the LAR.

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    • "In contrast, eotaxin-3 might be preferentially secreted at later time points when a TH2-dominant inflammatory state is observed. This hypothesis is supported by studies demonstrating that eotaxin-3, but not eotaxin-1, expression in bronchial mucosa is increased after allergen challenge in asthmatic individuals [35], [36]. "
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    ABSTRACT: Airway epithelial cells play a central role in the physiopathology of asthma. They release eotaxins when treated with T(H)2 cytokines such as interleukin (IL)-4 or IL-13, and these chemokines attract eosinophils and potentiate the biosynthesis of cysteinyl leukotrienes (cysLTs), which in turn induce bronchoconstriction and mucus secretion. These effects of cysLTs mainly mediated by CysLT(1) and CysLT(2) receptors on epithelial cell functions remain largely undefined. Because the release of inflammatory cytokines, eotaxins, and cysLTs occur relatively at the same time and location in the lung tissue, we hypothesized that they regulate inflammation cooperatively rather than redundantly. We therefore investigated whether cysLTs and the T(H)2 cytokines would act in concert to augment the release of eotaxins by airway epithelial cells. A549 cells or human primary bronchial epithelial cells were incubated with or without IL-4, IL-13, and/or LTD(4). The release of eotaxin-3 and the expression of cysLT receptors were assessed by ELISA, RT-PCR, and flow cytometry, respectively. IL-4 and IL-13 induced the release of eotaxin-3 by airway epithelial cells. LTD(4) weakly induced the release of eotaxin-3 but clearly potentiated the IL-13-induced eotaxin-3 release. LTD(4) had no effect on IL-4-stimulated cells. Epithelial cells expressed CysLT(1) but not CysLT(2). CysLT(1) expression was increased by IL-13 but not by IL-4 and/or LTD(4). Importantly, the upregulation of CysLT(1) by IL-13 preceded eotaxin-3 release. These results demonstrate a stepwise cooperation between IL-13 and LTD(4). IL-13 upregulates CysLT(1) expression and consequently the response to cysLTs This results in an increased release of eotaxin-3 by epithelial cells which at its turn increases the recruitment of leukocytes and their biosynthesis of cysLTs. This positive amplification loop involving epithelial cells and leukocytes could be implicated in the recruitment of eosinophils observed in asthmatics.
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    • "In contrast, CCL26 expression was dramatically upregulated (to 100-fold) in asthmatics 24 h following allergen exposure (Berkman and others 2001). Numbers of biopsy cells expressing CCL26 and CCL24, but not CCL11, correlated signifi cantly with the magnitude of the late asthmatic response (Ravensberg and others 2005). Th2-type cytokines induce release of signifi cant amounts of the eotaxins from both bronchial and alveolar type II cells (Komiya and others 2003; Yamamoto and others 2004; Heiman and others 2005). "
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    • "Studies in humans showed increased levels of eotaxin and eotaxin-2 in stable asthmatics when compared to healthy controls, whereas eotaxin-3 was only significantly increased after allergen challenge (Berkman et al., 2001) suggesting a role for eotaxin-3 in the allergen-induced eosinophil recruitment. Results from our own laboratory suggested that both eotaxin-2 and -3 are involved in eosinophil recruitment following allergen exposure in asthmatics (Ravensberg et al., 2005). Finally, injection of allergen into the skin of atopic subjects revealed that eotaxin-2 expression correlated with the late-phase influx of eosinophils (Ying et al., 1999). "
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