Teran L M, Mochizuki M, Bartels J, Valencia E L, Nakajima T, Hirai K, Schröder J M
Department of Allergy and Dermatology, University of Kiel, Kiel, Germany.
Am J Respir Cell Mol Biol. 1999 Apr;20(4):777-86. doi: 10.1165/ajrcmb.20.4.3508.
Eosinophils (Eos) and fibroblasts are known to play a major role in the pathogenesis of bronchial asthma and fibrotic lung disease. Therefore, we investigated whether Th1 and Th2 cytokines stimulate the production of Eo-activating chemokines by lung fibroblasts. Analyses of the culture supernatant using multiple steps of high-performance liquid chromatography demonstrated that interleukin (IL)-4 preferentially stimulates lung fibroblasts to secrete a peak of eosinophil chemotactic activity (ECA) which, upon N-terminal analyses, showed similar sequence to eotaxin, whereas interferon (IFN)-gamma had negligible effect on the release of this chemokine. In contrast, tumor necrosis factor (TNF)-alpha stimulated lung fibroblasts to release two peaks of activity that were found to correspond to eotaxin and regulated on activation, normal T cells expressed and secreted (RANTES), respectively. Interestingly, IL-4 synergized with TNF-alpha to increase greatly the production of three biochemically distinct eotaxin forms. In contrast, IFN-gamma synergized with TNF-alpha to increase RANTES production. Neither IL-2, IL-5, IL-6 nor IL-10 had an effect on lung fibroblasts' capacity to express or release eotaxin and RANTES. Upon appropriate cytokine stimulation, lung fibroblasts were also found to express messenger RNA for monocyte chemotactic protein (MCP)-3 and MCP-4 but not eotaxin-2. However, no ECA like MCP-3 or MCP-4 was detected. These observations suggest that the release of Th1 or Th2 cytokines in the lung tissue polarizes lung fibroblasts to produce either RANTES or eotaxin as major Eo attractants.
嗜酸性粒细胞（Eos）和成纤维细胞在支气管哮喘和肺纤维化疾病的发病机制中起着重要作用。因此，我们研究了Th1和Th2细胞因子是否刺激肺成纤维细胞产生嗜酸性粒细胞激活趋化因子。使用多步高效液相色谱法对培养上清液进行分析表明，白细胞介素（IL）-4优先刺激肺成纤维细胞分泌嗜酸性粒细胞趋化活性（ECA）峰，经N端分析，其序列与嗜酸性粒细胞趋化蛋白相似，而干扰素（IFN）-γ对该趋化因子的释放影响可忽略不计。相比之下，肿瘤坏死因子（TNF）-α刺激肺成纤维细胞释放两个活性峰，分别对应嗜酸性粒细胞趋化蛋白和对激活有调节作用的正常T细胞表达和分泌的趋化因子（RANTES）。有趣的是，IL-4与TNF-α协同作用，大大增加了三种生化性质不同的嗜酸性粒细胞趋化蛋白形式的产生。相反，IFN-γ与TNF-α协同作用，增加RANTES的产生。IL-2、IL-5、IL-6和IL-10对肺成纤维细胞表达或释放嗜酸性粒细胞趋化蛋白和RANTES的能力均无影响。在适当的细胞因子刺激下，还发现肺成纤维细胞表达单核细胞趋化蛋白（MCP）-3和MCP-4的信使核糖核酸，但不表达嗜酸性粒细胞趋化蛋白-2。然而，未检测到类似MCP-3或MCP-4的ECA。这些观察结果表明，肺组织中Th1或Th2细胞因子的释放使肺成纤维细胞极化，产生RANTES或嗜酸性粒细胞趋化蛋白作为主要的嗜酸性粒细胞吸引剂。
