Increased cAMP in Monocytes Augments Notch Signaling Mechanisms by Elevating RBP-J and Transducin-like Enhancer of Split (TLE)
Increased cAMP in Monocytes Augments Notch Signaling Mechanisms by Elevating RBP-J and Transducin-like Enhancer of Split (TLE)
复制标题
DOI：
10.1074/jbc.m113.465120
复制
发表时间：
2013-07-26
影响因子：
4.8
通讯作者：
Ballard, Jimmy D.
中科院分区：
文献类型：
--
作者：
Larabee, Jason L.;Shakir, Salika M.;Ballard, Jimmy D.
在先天性免疫系统的细胞中，细胞内cAMP的病理性增加减弱免疫应答并有助于细菌如炭疽杆菌的感染。在这项工作中，cAMP从B。炭疽水肿毒素（ET）被发现激活小鼠巨噬细胞和人单核细胞中的Notch信号通路。ET以及PKA的细胞渗透性激活剂诱导Notch靶基因（HES 1、HEY 1、IL 2 RA和IL 7 R），并且能够显著增强Toll样受体配体对这些Notch靶基因的诱导。升高的cAMP还导致Groucho/转导素样分裂增强子（TLE）水平增加，并导致由TLE和Notch靶点Hes 1组成的转录阻遏物复合物的量增加。为了阐明ET激活Notch信号传导的机制，对Notch信号传导的组分进行了检测，结果显示ET增加了J位点的重组识别序列结合蛋白（RBP-J）的水平，RBP-J是一种DNA结合蛋白，也是Notch信号传导的主要转录调节因子。过表达研究表明RBP-J足以激活Notch信号传导并增强LPS诱导的Notch信号传导。进一步研究ET激活Notch信号通路的机制发现，cAMP激活的转录因子C/EBP参与了Notch信号通路的激活并上调RBP-J的表达。这些研究表明，cAMP激活Notch信号通路并增加TLE的表达，这可能是cAMP抑制免疫应答的重要机制。
In cells of the innate immune system, pathological increases in intracellular cAMP attenuate immune responses and contribute to infections by bacteria such as Bacillus anthracis. In this work, cAMP from B. anthracis edema toxin (ET) is found to activate the Notch signaling pathway in both mouse macrophages and human monocytes. ET as well as a cell-permeable activator of PKA induce Notch target genes (HES1, HEY1, IL2RA, and IL7R) and are able to significantly enhance the induction of these Notch target genes by a Toll-like receptor ligand. Elevated cAMP also resulted in increased levels of Groucho/transducin-like enhancer of Split (TLE) and led to increased amounts of a transcriptional repressor complex consisting of TLE and the Notch target Hes1. To address the mechanism used by ET to activate Notch signaling, components of Notch signaling were examined, and results revealed that ET increased levels of recombinant recognition sequence binding protein at the J site (RBP-J), a DNA binding protein and principal transcriptional regulator of Notch signaling. Overexpression studies indicated that RBP-J was sufficient to activate Notch signaling and potentiate LPS-induced Notch signaling. Further examination of the mechanism used by ET to activate Notch signaling revealed that C/EBP , a transcription factor activated by cAMP, helped activate Notch signaling and up-regulated RBP-J. These studies demonstrate that cAMP activates Notch signaling and increases the expression of TLE, which could be an important mechanism utilized by cAMP to suppress immune responses.