Guanine nucleotide exchange factor-H1 promotes inflammatory cytokine production and intracellular mycobacterial elimination in macrophages
Guanine nucleotide exchange factor-H1 promotes inflammatory cytokine production and intracellular mycobacterial elimination in macrophages
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鸟嘌呤核苷酸交换因子-H1促进巨噬细胞炎症细胞因子的产生和细胞内分枝杆菌的消除
DOI：
10.1080/15384101.2017.1347739
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发表时间：
2017-01-01
期刊：
影响因子：
4.3
通讯作者：
Ma, Li
中科院分区：
文献类型：
--
作者：
Wang, Hui;Wang, Jinli;Ma, Li
引起结核病的结核分枝杆菌 (M.tb) 是一种适应宿主的细胞内病原体，由于其具有阻止吞噬溶酶体生物发生的能力，因此可以生活在巨噬细胞内。鸟嘌呤核苷酸交换因子 H1 (GEF-H1) 可能通过介导微管和肌动蛋白细胞骨架之间的串扰来促进巨噬细胞对细菌的吞噬。它在志贺氏菌感染中的作用已被确定，但对于 GEF-H1 在分枝杆菌感染中的作用知之甚少。在本研究中，我们证明 GEF-H1 是巨噬细胞介导的抗分枝杆菌反应的关键调节因子。我们发现分枝杆菌感染期间巨噬细胞中 GEF-H1 的 mRNA 和蛋白表达水平均显着上调。此外，用特异性 siRNA 沉默 GEF-H1 可减少 p38 丝裂原激活蛋白激酶和 TANK 结合激酶 1 的磷酸化以及白细胞介素 1 (IL-1)、IL-6 和干扰素 (IFN-) 的表达，而不影响一氧化氮的产生或自噬。重要的是，GEF-H1 耗竭减弱了巨噬细胞介导的分枝杆菌吞噬作用和消除作用。总而言之，我们的数据支持 GEF-H1 是炎症细胞因子产生和分枝杆菌消除的新型调节剂，并可能作为结核病临床治疗的新型潜在靶点。
Mycobacterium tuberculosis (M.tb), which causes tuberculosis, is a host-adapted intracellular pathogen that can live within macrophages owning to its ability to arrest phagolysosome biogenesis. The guanine nucleotide exchange factor H1 (GEF-H1) may contribute to the phagocytosis of bacteria by macrophages through mediating the crosstalk between microtubules and the actin cytoskeleton. Its role in Shigella infection has been determined but little is known about the role of GEF-H1 in mycobacterial infection. In the present study, we demonstrated that GEF-H1 functioned as a key regulator of the macrophage-mediated anti-mycobacterial response. We found that both mRNA and protein expression levels of GEF-H1 were significantly upregulated in macrophage during mycobacterial infection. Moreover, silencing of GEF-H1 with specific siRNAs reduced the phosphorylation of p38 mitogen-activated protein kinase and TANK binding kinase 1 as well as the expression of interleukin-1 (IL-1), IL-6, and interferon- (IFN-), without affecting nitric oxide production or autophagy. Importantly, GEF-H1 depletion attenuated macrophages-mediated mycobacterial phagocytosis and elimination. Taken together, our data supported that GEF-H1 was a novel regulator of inflammatory cytokine production and mycobacterial elimination, and may serve as a novel potential target for clinical treatment of tuberculosis.