Surfactant protein a modulates the inflammatory response in macrophages during tuberculosis
Surfactant protein a modulates the inflammatory response in macrophages during tuberculosis
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DOI：
10.1128/iai.72.2.645-650.2004
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发表时间：
2004-02-01
影响因子：
3.1
通讯作者：
Weiden, MD
中科院分区：
文献类型：
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作者：
Gold, JA;Hoshino, Y;Weiden, MD
结核病会导致免疫激活并增加肺部 I 型人类免疫缺陷病毒 (HIV-1) 的复制。然而，人类巨噬细胞分枝杆菌感染的体外模型并不能完全重现这些体内观察结果，表明还有其他宿主因素。表面活性蛋白 A (SP-A) 是肺部先天免疫的重要介质。通过支气管肺泡灌洗 (BAL) 测定人肺中的 SP-A 水平。结核病期间，仅在放射照相涉及的肺段中 SP-A 水平降低了三倍，并且在治疗 1 个月后水平恢复正常。 SP-A 水平与 BAIL 液中中性粒细胞的百分比呈负相关，表明低 SP-A 水平与肺部炎症增加有关。使用分化的THP-1巨噬细胞来测试降低SP-A水平对免疫功能的影响。在没有结核分枝杆菌感染的情况下，5 至 0.01 mug/ml 剂量范围的 SP-A 抑制白细胞介素 6 (IL-6) 的产生和 HIV-1 长末端重复序列 (LTR) 活性。在感染结核分枝杆菌的巨噬细胞中，SP-A 增强了 IL-6 的产生和 HIV-1 LTR 活性。为了更好地了解 SP-A 的作用，我们测量了 CAAT/增强子结合蛋白 beta (C/EBPbeta) 的表达，CAAT/EBPbeta 是调节 IL-6 和 HIV-1 LTR 的核心转录因子。在感染结核分枝杆菌的巨噬细胞中，SP-A 降低了 C/EBPbeta 显性失活亚型的表达。这些数据表明，即使在结核病患者中发现的低浓度 SP-A 也具有多效性。这种蛋白质会在感染时加剧炎症，并抑制未感染巨噬细胞的炎症，保护未受影响的肺段免受炎症的有害影响。
Tuberculosis leads to immune activation and increased human immunodeficiency virus type I (HIV-1) replication in the lung. However, in vitro models of mycobacterial infection of human macrophages do not fully reproduce these in vivo observations, suggesting that there are additional host factors. Surfactant protein A (SP-A) is an important mediator of innate immunity in the lung. SP-A levels were assayed in the human lung by using bronchoalveolar lavage (BAL). There was a threefold reduction in SP-A levels during tuberculosis only in the radiographically involved lung segments, and the levels returned to normal after I month of treatment. The SP-A levels were inversely correlated with the percentage of neutrophils in BAIL fluid, suggesting that low SP-A levels were associated with increased inflammation in the lung. Differentiated THP-1 macrophages were used to test the effect of decreasing SP-A levels on immune function. In the absence of infection with Mycobacterium tuberculosis, SP-A at doses ranging from 5 to 0.01 mug/ml inhibited both interieukin-6 (IL-6) production and HIV-1 long terminal repeat (LTR) activity. In macrophages infected with M. tuberculosis, SP-A augmented both IL-6 production and HIV-1 LTR activity. To better understand the effect of SP-A, we measured expression of CAAT/enhancer binding protein beta (C/EBPbeta), a transcription factor central to the regulation of IL-6 and the HIV-1 LTR. In macrophages infected with M. tuberculosis, SP-A reduced expression of a dominant negative isoform of C/EBPbeta. These data suggest that SP-A has pleiotropic effects even at the low concentrations found in tuberculosis patients. This protein augments inflammation in the presence of infection and inhibits inflammation in uninfected macrophages, protecting uninvolved lung segments from the deleterious effects of inflammation.