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Sphingosine kinase-1 (SphK-1) Regulates Mycobacterium Smegmatis Infection in Macrophages

Sphingosine kinase-1 (SphK-1) Regulates Mycobacterium Smegmatis Infection in Macrophages

Hridayesh Prakash, Anja Lüth, Natalia Grinkina, Daniela Holzer, Raj Wadgaonkar, Alexis Perez Gonzalez, Elsa Anes, Burkhard Kleuser

PLoS One. 2010 May 17;5(5):e10657.

PMID: 20498849

Abstract:

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-kappaB. This led to a reduction in the generation of NO and secretion of TNF-alpha 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-1(bright) phenotype of these macrophages. These findings thus suggested a novel antimycobacterial role of SphK-1 in macrophages.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP15639506-A	L-threo-Dihydrosphingosine		15639-50-6	Price

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