Modulation of gene expression in human macrophages treated with the anti-Leishmania pentavalent antimonial drug sodium stibogluconate
Modulation of gene expression in human macrophages treated with the anti-Leishmania pentavalent antimonial drug sodium stibogluconate
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DOI：
10.1128/aac.01183-07
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发表时间：
2008-02-01
影响因子：
4.9
通讯作者：
Ouellette, Marc
中科院分区：
文献类型：
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作者：
El Fadili, Karima;Imbeault, Michael;Ouellette, Marc
在哺乳动物宿主体内，多诺瓦利什曼原虫是一种强制性的细胞内原生动物寄生虫，它只在巨噬细胞的吞噬溶酶体中生存和繁殖。利什曼原虫的控制主要依靠化疗，主要是五价锑（SbV）与碳水化合物络合，形成stibogluconate钠（pentastam）或meglumine antimonate（葡聚糖）。SbV的作用方式尚不清楚。为了探索SbV对巨噬细胞基因表达的影响，采用Affymetrix聚焦阵列进行微阵列分析，比较了未经抑制葡萄糖酸钠处理和未经抑制葡萄糖酸钠处理的L. donovani感染和未感染的THP-1单核细胞的基因表达谱。在我们的实验条件下，SbV改变了少数宿主基因的表达，这与细胞是否感染利什曼原虫无关。利什曼原虫感染对宿主基因表达的调节作用较大。统计分析表明，8个基因的表达在SbV处理后至少改变了2倍，其中6个基因表达上调，2个基因表达下调。受SbV影响表达的一个基因是血红素加氧酶基因HMOX-1，这种变化在单核细胞系THP-1和原代人单核细胞源性巨噬细胞中都观察到。另一个受影响的途径是谷胱甘肽生物合成途径，在SbV处理下，谷氨酸-半胱氨酸连接酶修饰子亚基的表达增加。我们的分析表明，在我们的实验条件下，一些基因的表达在SbV治疗后发生了改变，其中一些编码蛋白可能与SbV尚未确定的作用模式有关。
Within the mammalian host, Leishmania donovani is an obligatory intracellular protozoan parasite that resides and multiplies exclusively in the phagolysosomes of macrophages. Leishmania control relies primarily on chemotherapy, with the mainstay being pentavalent antimony (SbV) complexed to carbohydrates in the form of sodium stibogluconate (Pentostam) or meglumine antimoniate (Glucantime). The mode of action of SbV is still not known precisely. To explore the effect of SbV on macrophage gene expression, a microarray analysis was performed using Affymetrix focus arrays to compare gene expression profiles in noninfected and L. donovani-infected THP-1 monocytic cells treated or not treated with sodium stibogluconate. Under our experimental conditions, SbV changed the expression of a few host genes, and this was independent of whether cells were infected or not infected with Leishmania. Leishmania infection had a greater effect on the modulation of host gene expression. Statistical analyses have indicated that the expression of eight genes was modified by at least twofold upon SbV treatment, with six genes upregulated and two genes downregulated. One gene whose expression was affected by SbV was the heme oxygenase gene HMOX-1, and this change was observed both in the monocytic cell line THP-1 and in primary human monocyte-derived macrophages. Another pathway that was affected was the glutathione biosynthesis pathway, where the expression of the glutamate-cysteine ligase modifier subunit was increased upon SbV treatment. Our analysis has suggested that, under our experimental conditions, the expression of a few genes is altered upon SbV treatment, and some of these encoded proteins may be implicated in the yet-to-be-defined mode of action of SbV.