NOTCH1 up-regulation and signaling involved in Mycobacterium bovis BCG-induced SOCS3 expression in macrophages
NOTCH1 up-regulation and signaling involved in Mycobacterium bovis BCG-induced SOCS3 expression in macrophages
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DOI：
10.1074/jbc.m709960200
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发表时间：
2008-05-02
影响因子：
4.8
通讯作者：
Balaji, Kithiganahalli Narayanaswamy
中科院分区：
文献类型：
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作者：
Narayana, Yeddula;Balaji, Kithiganahalli Narayanaswamy
细胞因子信号转导抑制因子（SOCS）3是细胞因子信号转导的关键负调节因子，由牛分枝杆菌卡介苗（M. bovis BCG）。然而，对分枝杆菌介导的SOCS 3诱导的早期受体近端信号传导机制知之甚少。我们在这里首次证明，M。牛BCG上调NOTCH 1并激活NOTCH 1信号通路，导致SOCS 3的表达。我们发现，在感染的巨噬细胞中干扰Notch信号导致SOCS 3表达的显著减少。此外，在RAW 264.7巨噬细胞中Notch 1胞内结构域的强制表达诱导SOCS 3的表达，这可以被M.牛卡介苗Toll样受体（TLR）2信号转导的干扰导致SOCS 3水平和NOTCH 1靶基因Hes 1表达显著降低。MyD 88的下调导致SOCS 3表达的显著降低，暗示TLR 2-MyD 88轴在M.牛BCG触发的信号传导。而M.牛BCG在感染来自TLR 4缺陷型C3 H/HeJ小鼠的巨噬细胞后也保持不变。更重要的是，信号扰动数据表明参与的成员之间的串扰的磷酸肌醇3-激酶和促分裂原活化蛋白激酶级联与NOTCH 1信号在SOCS 3的表达。此外，SOCS 3表达需要NOTCH 1介导的无毛抑制因子（CSL）和核因子-κ B向SOCS 3启动子的募集。总的来说，这些结果暗示了在用细胞内杆菌样M感染巨噬细胞后SOCS 3的诱导表达期间的NOTCH 1信号传导。牛卡介苗
Suppressor of cytokine signaling ( SOCS) 3 is a critical negative regulator of cytokine signaling and is induced by Mycobacterium bovis Bacille Calmette-Guerin ( M. bovis BCG) in mouse macrophages. However, little is known about the early receptor proximal signaling mechanisms underlying mycobacteria-mediated induction of SOCS3. We demonstrate here for the first time that M. bovis BCG up-regulates NOTCH1 and activates the NOTCH1 signaling pathway, leading to the expression of SOCS3. We show that perturbing Notch signaling in infected macrophages results in the marked reduction in the expression of SOCS3. Furthermore, enforced expression of the Notch1 intracellular domain in RAW 264.7 macrophages induces the expression of SOCS3, which can be further potentiated by M. bovis BCG. The perturbation of Toll-like receptor (TLR) 2 signaling resulted in marked reduction in SOCS3 levels and expression of the NOTCH1 target gene, Hes1. The down-regulation of MyD88 resulted in a significant decrease in SOCS3 expression, implicating the role of the TLR2-MyD88 axis in M. bovis BCG-triggered signaling. However, the SOCS3 inducing ability of M. bovis BCG remains unaltered also upon infection of macrophages from TLR4-defective C3H/HeJ mice. More importantly, signaling perturbation data suggest the involvement of crosstalk among members of the phosphoinositide 3-kinase and mitogen-activated protein kinase cascades with NOTCH1 signaling in SOCS3 expression. Furthermore, SOCS3 expression requires the NOTCH1-mediated recruitment of Suppressor of Hairless (CSL) and nuclear factor-kappa B to the Socs3 promoter. Overall, these results implicate NOTCH1 signaling during inducible expression of SOCS3 following infection of macrophages with an intracellular bacillus-like M. bovis BCG.