sphingosine-kinase and Tuberculosis

CCL5 is a key in limiting mycobacterial infection. Although NF-kappaB has been implicated, signaling cascades involved in CCL5 production by epithelial cells following infection with Mycobacterium bovis BCG are still not defined. Here we show that using pharmacological inhibition of sphingosine kinase (SPK), striking inhibition of M. bovis BCG-induced CCL5 protein was observed. Phosphatidylinositol 3-kinase (PI3K) and Akt were also important for CCL5 production by epithelial cells infected with M. bovis BCG. Moreover, there was increased activation of PI3K, IKK/alphabeta and NF-kappaB in A549 cells infected with M. bovis BCG. Importantly, the PI3K activation was dependent on SPK. Finally, M. bovis BCG increases the recruitment of p300 with NF-kappaB in A549 cells. Together, these studies are the first to show that M. bovis BCG-induced CCL5 secretion is dependent on the SPK/PI3K/Akt/NF-kappaB and p300 signaling pathway. The regulatory pathways of M. bovis BCG-induced CCL5 production can potentially be exploited therapeutically.

Topics: BCG Vaccine; Blotting, Western; Cell Line; Chemokine CCL5; E1A-Associated p300 Protein; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Humans; Immunoprecipitation; NF-kappa B; Phosphatidylinositol 3-Kinases; Phosphotransferases (Alcohol Group Acceptor); Proto-Oncogene Proteins c-akt; Signal Transduction; Tuberculosis