Unique, Intersecting, and Overlapping Roles of C/EBP β and CREB in Cells of the Innate Immune System.
Unique, Intersecting, and Overlapping Roles of C/EBP β and CREB in Cells of the Innate Immune System.
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DOI：
10.1038/s41598-018-35184-y
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发表时间：
2018-11-16
影响因子：
4.6
通讯作者：
Ballard JD
中科院分区：
文献类型：
--
作者：
Larabee JL;Hauck G;Ballard JD
CREB和C/EBP β信号通路在炎症过程中受到调节，也被炭疽杆菌水肿毒素（ET）靶向，但这些因素如何单独和共同促进免疫细胞功能的变化还知之甚少。使用CRISPR/Cas9基因编辑，生成缺乏CREB和C/EBP β亚型的巨噬细胞系，并分析对LPS、ET和IL-4的反应变化。缺乏C/EBP β的巨噬细胞抑制IL-10和Arg 1的诱导，而IL-6在这些细胞中暴露于LPS后增加。对C/EBP β亚型的检查表明，38 kDa亚型对于IL-10和Arg 1的表达是必需的。CREB和C/EBP β与人PBMC染色体上靶点结合的ChIP-Seq分析确定了两种因子结合重叠的几个区域，表明基因靶向或协同效应相似。基于ChIP-Seq数据，确定了一组先前未知的CREB和C/EBP β靶点，包括VNN 2、GINS 4、CTNNBL 1和SULF 2等基因。转录辅阻遏物的亚型，分裂的转导素样增强子（TLE），也被发现有CREB和C/EBP β结合其启动子，并被ET上调。最后，我们探讨了由腺瘤性结肠息肉病（APC）和PKA组成的蛋白复合物对C/EBP β调控的可能层。总的来说，这些数据为CREB和C/EBP β作为免疫信号调节剂和重要细菌毒力因子的靶点的作用提供了新的见解。
CREB and C/EBP β signaling pathways are modulated during inflammation and also targeted by Bacillus anthracis edema toxin (ET), but how these factors individually and jointly contribute to changes in immune cell function is poorly understood. Using CRISPR/Cas9 gene editing, macrophage cell lines lacking CREB and isoforms of C/EBP β were generated and analyzed for changes in responses to LPS, ET, and IL-4. Macrophages lacking C/EBP β suppressed induction of IL-10 and Arg1, while IL-6 was increased in these cells following exposure to LPS. Examination of C/EBP β isoforms indicated the 38 kDa isoform was necessary for the expression of IL-10 and Arg1. ChIP-Seq analysis of CREB and C/EBP β binding to targets on the chromosome of human PBMC identified several regions where both factors overlapped in their binding, suggesting similar gene targeting or cooperative effects. Based on the ChIP-Seq data, a panel of previously unknown targets of CREB and C/EBP β was identified and includes genes such as VNN2, GINS4, CTNNBL1, and SULF2. Isoforms of a transcriptional corepressor, transducin-like enhancer of Split (TLE), were also found to have CREB and C/EBP β binding their promoter and were up regulated by ET. Finally, we explore a possible layer of C/EBP β regulation by a protein complex consisting of adenomatous polyposis coli (APC) and PKA. Collectively, these data provide new insights into the role of CREB and C/EBP β as immunosignaling regulators and targets of an important bacterial virulence factor.
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影响因子：
4.4
作者：
Everett LJ;Le Lay J;Lukovac S;Bernstein D;Steger DJ;Lazar MA;Kaestner KH
通讯作者：
Kaestner KH
DOI：
10.1073/pnas.91.12.5647
发表时间：
1994-06-07
影响因子：
11.1
作者：
HUMMLER, E;COLE, TJ;SCHUTZ, G
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SCHUTZ, G
DOI：
10.1073/pnas.79.10.3162
发表时间：
1982-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
LEPPLA, SH
通讯作者：
LEPPLA, SH
影响因子：
4.8
作者：
Larabee, Jason L.;Shakir, Salika M.;Ballard, Jimmy D.
通讯作者：
Ballard, Jimmy D.
DOI：
10.1073/pnas.1511380113
发表时间：
2016-02-16
影响因子：
11.1
作者：
Ramasamy, Selvi;Saez, Borja;Sweetser, David A.
通讯作者：
Sweetser, David A.