Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Québec, QC, Canada.
PLoS One. 2012;7(8):e43544. doi: 10.1371/journal.pone.0043544. Epub 2012 Aug 31.
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.
气道上皮细胞在哮喘的病理生理学中起着核心作用。当它们受到 T(H)2 细胞因子（如白细胞介素（IL）-4 或 IL-13）的治疗时，它们会释放嗜酸性粒细胞趋化因子，这些趋化因子吸引嗜酸性粒细胞并增强半胱氨酰白三烯（cysLTs）的生物合成，这反过来又引起支气管收缩和粘液分泌。这些 cysLTs 的作用主要通过上皮细胞功能上的 CysLT(1)和 CysLT(2)受体介导，但尚未得到充分定义。由于炎症细胞因子、嗜酸性粒细胞趋化因子和 cysLTs 的释放相对同时发生并且发生在肺组织的同一位置，因此我们假设它们会协同而不是冗余地调节炎症。因此，我们研究了 cysLTs 和 T(H)2 细胞因子是否会协同作用以增强气道上皮细胞释放嗜酸性粒细胞趋化因子。
用或不用 IL-4、IL-13 和/或 LTD(4)孵育 A549 细胞或人原代支气管上皮细胞。通过 ELISA、RT-PCR 和流式细胞术分别评估嗜酸性粒细胞趋化因子-3 的释放和 cysLT 受体的表达。
IL-4 和 IL-13 诱导气道上皮细胞释放嗜酸性粒细胞趋化因子-3。LTD(4) 弱诱导嗜酸性粒细胞趋化因子-3 的释放，但明显增强 IL-13 诱导的嗜酸性粒细胞趋化因子-3 释放。LTD(4) 对 IL-4 刺激的细胞没有影响。上皮细胞表达 CysLT(1)但不表达 CysLT(2)。IL-13 增加 CysLT(1)的表达，但不是 IL-4 和/或 LTD(4)。重要的是，IL-13 对 CysLT(1)的上调先于嗜酸性粒细胞趋化因子-3 的释放。
这些结果表明 IL-13 和 LTD(4)之间存在逐步合作。IL-13 上调 CysLT(1)的表达，从而增加对 cysLTs 的反应。这导致上皮细胞释放更多的嗜酸性粒细胞趋化因子-3，从而增加白细胞的募集及其 cysLTs 的生物合成。这种涉及上皮细胞和白细胞的正反馈环可能与哮喘患者中观察到的嗜酸性粒细胞募集有关。
