Abstract
IntroductionAirway epithelial cells play a central role in the physiopathology of asthma. They release eotaxins when treated with TH2 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 CysLT1 and CysLT2 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 TH2 cytokines would act in concert to augment the release of eotaxins by airway epithelial cells.MethodsA549 cells or human primary bronchial epithelial cells were incubated with or without IL-4, IL-13, and/or LTD4. The release of eotaxin-3 and the expression of cysLT receptors were assessed by ELISA, RT-PCR, and flow cytometry, respectively.ResultsIL-4 and IL-13 induced the release of eotaxin-3 by airway epithelial cells. LTD4 weakly induced the release of eotaxin-3 but clearly potentiated the IL-13-induced eotaxin-3 release. LTD4 had no effect on IL-4-stimulated cells. Epithelial cells expressed CysLT1 but not CysLT2. CysLT1 expression was increased by IL-13 but not by IL-4 and/or LTD4. Importantly, the upregulation of CysLT1 by IL-13 preceded eotaxin-3 release.ConclusionsThese results demonstrate a stepwise cooperation between IL-13 and LTD4. IL-13 upregulates CysLT1 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.
Highlights
Airway epithelial cells play a central role in the physiopathology of asthma
IL-13 upregulates CysLT1 expression and the response to cysteinyl leukotrienes (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
In a first series of experiments, we evaluated the effect of IL-13 and LTD4 on the release of eotaxins following a 24 hours incubation of A549 airway epithelial cells with these mediators
Summary
Airway epithelial cells play a central role in the physiopathology of asthma They release eotaxins when treated with TH2 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 CysLT1 and CysLT2 receptors on epithelial cell functions remain largely undefined. Eotaxin-1 is secreted by eosinophils, macrophages, lymphocytes, fibroblasts, smooth muscle and endothelial cells, whereas eotaxin-2 and eotaxin-3 are mainly released by epithelial and endothelial cells [4] Among these cell type, epithelial cells are the major source of eotaxins and principally release high levels of eotaxin-3 [2,5,6]. The TH2 cytokines IL-4 and IL-13 enhance the secretion of all eotaxins, whereas the TH1 cytokines interferon-c and tumor necrosis factor-a exclusively promote the release of eotaxin-1 [7,8]
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