Clofazimine modulates the expression of lipid metabolism proteins in Mycobacterium leprae-infected macrophages.
Clofazimine modulates the expression of lipid metabolism proteins in Mycobacterium leprae-infected macrophages.
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DOI：
10.1371/journal.pntd.0001936
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发表时间：
2012
影响因子：
3.8
通讯作者：
Suzuki K
中科院分区：
文献类型：
--
作者：
Degang Y;Akama T;Hara T;Tanigawa K;Ishido Y;Gidoh M;Makino M;Ishii N;Suzuki K
麻风分枝杆菌（M.麻风）在泡沫状、充满脂质的吞噬体内的巨噬细胞内生活和复制。脂质为分枝杆菌提供必需的营养，而M.麻风感染调节与脂质代谢相关的重要宿主蛋白质的表达。因此，M.麻风感染增加了嗜脂蛋白/脂肪分化相关蛋白（ADRP）的表达，降低了对脂肪敏感的脂肪酶（HSL），促进了适合于M.麻风病人麻风病人的皮肤涂片标本中检测不到HSL水平，但在多药治疗（MDT）后不久再次出现。本研究检测MDT组分对体外宿主脂质代谢的影响，以及利福平、氨苯砜和氯法齐明对THP-1细胞ADRP和HSL表达的影响。氯法齐明可降低M.而HSL组则增加。利福平和氨苯砜对ADRP和HSL表达水平无显著影响。感染M.用氯法齐明治疗M.用氯法齐明治疗后48 h，麻风感染率显著降低。这种作用在没有M的细胞中不明显。麻风病感染在临床标本中，治疗后ADRP表达降低，HSL表达升高。这些结果表明，氯法齐明调节M。通过调节ADRP和HSL的表达来抑制麻风感染的巨噬细胞。它还诱导M.麻风病感染细胞由此导致的脂质蓄积减少、脂解增加和先天免疫激活可能是氯法齐明的一些关键作用。麻风病是由麻风分枝杆菌（Mycobacterium leprae，M.麻风）是一种古老的传染病，仍然是导致残疾的主要传染性原因。感染M.麻风菌生活在含有大量脂质的宿主巨噬细胞内，这被认为是M.麻风病在宿主细胞中生存M.麻风感染增加了巨噬细胞中的脂质积累，并减少了脂质的代谢分解（catalysis）。此外，麻风病的多药治疗（MDT）逆转了感染对脂质代谢调节的影响。因此，我们的目的是使用培养的人巨噬细胞，以确定这三个MDT药物（氯法齐明，氨苯砜，或利福平）是负责这种效果。我们发现，只有氯法齐明影响脂质积累和catalysts在M。麻风病感染的细胞。当细胞培养基中加入氯法齐明时，细胞中积累的脂质量减少。氯法齐明也能激活M.麻风病感染细胞提示氯法齐明抗麻风作用的机制可能与调节脂质代谢和激活机体免疫反应有关。麻风病感染的宿主细胞
Mycobacterium leprae (M. leprae) lives and replicates within macrophages in a foamy, lipid-laden phagosome. The lipids provide essential nutrition for the mycobacteria, and M. leprae infection modulates expression of important host proteins related to lipid metabolism. Thus, M. leprae infection increases the expression of adipophilin/adipose differentiation-related protein (ADRP) and decreases hormone-sensitive lipase (HSL), facilitating the accumulation and maintenance of lipid-rich environments suitable for the intracellular survival of M. leprae. HSL levels are not detectable in skin smear specimens taken from leprosy patients, but re-appear shortly after multidrug therapy (MDT). This study examined the effect of MDT components on host lipid metabolism in vitro, and the outcome of rifampicin, dapsone and clofazimine treatment on ADRP and HSL expression in THP-1 cells. Clofazimine attenuated the mRNA and protein levels of ADRP in M. leprae-infected cells, while those of HSL were increased. Rifampicin and dapsone did not show any significant effects on ADRP and HSL expression levels. A transient increase of interferon (IFN)-β and IFN-γ mRNA was also observed in cells infected with M. leprae and treated with clofazimine. Lipid droplets accumulated by M. leprae-infection were significantly decreased 48 h after clofazimine treatment. Such effects were not evident in cells without M. leprae infection. In clinical samples, ADRP expression was decreased and HSL expression was increased after treatment. These results suggest that clofazimine modulates lipid metabolism in M. leprae-infected macrophages by modulating the expression of ADRP and HSL. It also induces IFN production in M. leprae-infected cells. The resultant decrease in lipid accumulation, increase in lipolysis, and activation of innate immunity may be some of the key actions of clofazimine. Leprosy, caused by Mycobacterium leprae (M. leprae), is an ancient infectious disease that remains the leading infectious cause of disability. After infection, M. leprae lives inside host macrophages that contain a large amount of lipids, which is thought to be an essential microenvironment for M. leprae to survive in host cells. M. leprae infection increases lipid accumulation in macrophages and decreases the metabolic breakdown of lipids (catabolism). In addition, the treatment of leprosy with multidrug therapy (MDT) reverses the effect of infection on the modulation of lipid metabolism. We therefore aimed to use cultured human macrophage cells to determine which of the three MDT drugs (clofazimine, dapsone, or rifampicin) is responsible for this effect. We found that only clofazimine affects lipid accumulation and catabolism in M. leprae-infected cells in vitro. The amounts of lipids accumulated in the cells decreased when clofazimine was added to the cell culture medium. Clofazimine also activated immune responses in M. leprae-infected cells. These results suggest that the effectiveness of clofazimine against leprosy is due to the modulation of lipid metabolism and activation of immune reactions in M. leprae-infected host cells.