Méndez-Samperio Patricia, Pérez Aline, Trejo Artemisa
Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, IPN, Prol. Carpio y Plan de Ayala, México, D.F. 11340, Mexico.
Cell Immunol. 2007 Oct;249(2):94-100. doi: 10.1016/j.cellimm.2007.11.008. Epub 2008 Jan 3.
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.
CCL5是限制分枝杆菌感染的关键因素。尽管已有研究表明核因子κB（NF-κB）与之相关，但卡介苗（Mycobacterium bovis BCG）感染后上皮细胞产生CCL5所涉及的信号级联仍不明确。在此，我们发现，通过对鞘氨醇激酶（SPK）进行药理学抑制，可显著抑制卡介苗诱导的CCL5蛋白产生。磷脂酰肌醇3激酶（PI3K）和蛋白激酶B（Akt）对卡介苗感染的上皮细胞产生CCL5也很重要。此外，感染卡介苗的A549细胞中PI3K、IKK/αβ和NF-κB的激活增加。重要的是，PI3K的激活依赖于SPK。最后，卡介苗增加了A549细胞中p300与NF-κB的募集。总之，这些研究首次表明，卡介苗诱导的CCL5分泌依赖于SPK/PI3K/Akt/NF-κB和p300信号通路。卡介苗诱导CCL5产生的调控途径可能具有潜在的治疗应用价值。
