Differential regulation of cytokine release and leukocyte migration by lipopolysaccharide-stimulated primary human lung alveolar type II epithelial cells and macrophages
Differential regulation of cytokine release and leukocyte migration by lipopolysaccharide-stimulated primary human lung alveolar type II epithelial cells and macrophages
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DOI：
10.4049/jimmunol.178.1.463
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发表时间：
2007-01-01
影响因子：
4.4
通讯作者：
Tetley, Teresa D.
中科院分区：
文献类型：
--
作者：
Thorley, Andrew J.;Ford, Paul A.;Tetley, Teresa D.
细菌定植是许多与细胞因子水平升高和白细胞募集增加相关的肺部疾病的次要特征。我们假设，除了巨噬细胞，上皮细胞将是这些介质的重要来源。我们研究了LPS（0、10、100和1000 ng/ml LPS，长达24 h）对原代人肺巨噬细胞和肺泡II型上皮细胞（ATII;分离自切除的肺组织）的影响。虽然巨噬细胞产生更高水平的细胞因子TNF-α和IL-1 β（p < 0.0001），但ATII细胞产生更高水平的趋化因子MCP-1、IL-8和生长相关癌基因α（p < 0.001），且呈时间和浓度依赖性。巨噬细胞（而不是ATII细胞）对LPS的反应需要激活ERK 1/2和p38 MAPK信号级联;磷酸化ERK 1/2在ATII细胞中组成性上调。在LPS暴露期间阻断Ab对TNF-α和IL-1 β的作用显示ATII细胞（不是巨噬细胞）MCP-1释放依赖于IL-1 β和TNF-α的自分泌作用（p < 0.003，24 h）。ATH细胞释放IL-6依赖于TNF-α的自分泌效应（p < 0.006，24 h）。当TNF-α和IL-1 β都被阻断时，巨噬细胞IL-6释放被最有效地抑制（p < 0.03，24小时）。来自ATII细胞的条件培养基比来自巨噬细胞的条件培养基在体外刺激更多的白细胞迁移（p < 0.0002）。这些结果显示在LPS暴露后ATII细胞和巨噬细胞的细胞因子和趋化因子释放的差异活化。活化的肺泡上皮细胞是协调白细胞迁移至外周肺的趋化因子的重要来源;受刺激的巨噬细胞早期释放TNF-α和IL-1 β可能有助于肺泡上皮细胞活化和趋化因子产生。
Bacterial colonization is a secondary feature of many lung disorders associated with elevated cytokine levels and increased leukocyte recruitment. We hypothesized that, alongside macrophages, the epithelium would be an important source of these mediators. We investigated the effect of LPS (0, 10, 100, and 1000 ng/ml LPS, up to 24 h) on primary human lung macrophages and alveolar type II epithelial cells (ATII; isolated from resected lung tissue). Although macrophages produced higher levels of the cytokines TNF-alpha and IL-1 beta (p < 0.0001), ATII cells produced higher levels of chemokines MCP-1, IL-8, and growth-related oncogene a (p < 0.001), in a time- and concentration-dependent manner. Macrophage (but not ATII cell) responses to LPS required activation of ERK1/2 and p38 MAPK signaling cascades; phosphorylated ERK1/2 was constitutively up-regulated in ATII cells. Blocking Abs to TNF-alpha and IL-1 beta during LPS exposure showed that ATII cell (not macrophage) MCP-1 release depended on the autocrine effects of IL-1 beta and TNF-a (p < 0.003, 24 h). ATH cell release of IL-6 depended on autocrine effects of TNF-alpha (p < 0.006, 24 h). Macrophage IL-6 release was most effectively inhibited when both TNF-a and IL-1 beta were blocked (p < 0.03, 24 h). Conditioned media from ATII cells stimulated more leukocyte migration in vitro than conditioned media from macrophages (p < 0.0002). These results show differential activation of cytokine and chemokine release by ATII cells and macrophages following LPS exposure. Activated alveolar epithelium is an important source of chemokines that orchestrate leukocyte migration to the peripheral lung; early release of TNF-alpha and IL-1 beta by stimulated macrophages may contribute to alveolar epithelial cell activation and chemokine production.