Sphingosine kinase-1 (SphK-1) regulates Mycobacterium smegmatis infection in macrophages.
Sphingosine kinase-1 (SphK-1) regulates Mycobacterium smegmatis infection in macrophages.
复制标题
DOI：
10.1371/journal.pone.0010657
复制
发表时间：
2010-05-17
期刊：
影响因子：
3.7
通讯作者：
Kleuser B
中科院分区：
文献类型：
--
作者：
Prakash H;Lüth A;Grinkina N;Holzer D;Wadgaonkar R;Gonzalez AP;Anes E;Kleuser B
鞘氨醇激酶-1在巨噬细胞中介导耻垢分枝杆菌诱导的炎症反应，但其在控制感染中的作用迄今尚未报道。我们旨在揭示SphK-1在控制RAW 264.7巨噬细胞中耻垢支原体感染中的意义。我们的研究结果首次证明了SphK-1被D、L三邻二氢鞘氨醇（DHS， SphK-1的竞争性抑制剂）或SphK-1 siRNA选择性抑制，使RAW巨噬细胞对耻毛分枝杆菌感染敏感。这是由于iNOs、p38、pp-38、吞噬体晚期标志物LAMP-2的表达减少以及NF-κB的RelA （pp-65）亚基的稳定。这导致感染的巨噬细胞中NO的生成和TNF-α的分泌减少。同样，SphK-1的过表达使巨噬细胞对感染产生抗性，这是由于NO的生成以及iNOs、pp38和LAMP-2的表达增强。此外，我们的研究结果还揭示了SphK-1在耻垢分枝杆菌感染和巨噬细胞NO生成过程中对p38MAPK的新调控。SphK-1++感染的巨噬细胞中NO生成和iNOs表达增强，表明巨噬细胞具有M-1bright表型。这些发现提示SphK-1在巨噬细胞中具有新的抗真菌作用。
Sphingosine kinase-1 is known to mediate Mycobacterium smegmatis induced inflammatory responses in macrophages, but its role in controlling infection has not been reported to date. We aimed to unravel the significance of SphK-1 in controlling M. smegmatis infection in RAW 264.7 macrophages. Our results demonstrated for the first time that selective inhibition of SphK-1 by either D, L threo dihydrosphingosine (DHS; a competitive inhibitor of Sphk-1) or Sphk-1 siRNA rendered RAW macrophages sensitive to M. smegmatis infection. This was due to the reduction in the expression of iNOs, p38, pp-38, late phagosomal marker, LAMP-2 and stabilization of the RelA (pp-65) subunit of NF-κB. This led to a reduction in the generation of NO and secretion of TNF-α in infected macrophages. Congruently, overexpression of SphK-1 conferred resistance in macrophages to infection which was due to enhancement in the generation of NO and expression of iNOs, pp38 and LAMP-2. In addition, our results also unraveled a novel regulation of p38MAPK by SphK-1 during M. smegmatis infection and generation of NO in macrophages. Enhanced NO generation and expression of iNOs in SphK-1++ infected macrophages demonstrated their M-1bright phenotype of these macrophages. These findings thus suggested a novel antimycobacterial role of SphK-1 in macrophages.
登录
查看更多内容
影响因子：
3.4
作者：
Gutierrez, Maximiliano Gabriel;Gonzalez, Alexis Perez;Griffiths, Gareth
通讯作者：
Griffiths, Gareth
影响因子：
4.8
作者：
Allende, ML;Sasaki, T;Proia, RL
通讯作者：
Proia, RL
DOI：
10.1165/ajrcmb.25.5.4487
发表时间：
2001-11-01
影响因子：
6.4
作者：
Chan, ED;Chan, J;Schluger, NW
通讯作者：
Schluger, NW
影响因子：
3.8
作者：
Etard, JF;Ndiaye, I;Delaporte, E
通讯作者：
Delaporte, E
影响因子：
5.5
作者：
Edwards, Justin P.;Zhang, Xia;Mosser, David M.
通讯作者：
Mosser, David M.