Elevated cyclic AMP inhibits NF-kappa B-mediated transcription in human monocytic cells and endothelial cells
Elevated cyclic AMP inhibits NF-kappa B-mediated transcription in human monocytic cells and endothelial cells
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DOI：
10.1074/jbc.271.34.20828
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发表时间：
1996-08-23
影响因子：
4.8
通讯作者：
Mackman, N
中科院分区：
文献类型：
--
作者：
Ollivier, V;Parry, GCN;Mackman, N
NF-κ B/Rel转录因子家族调节活化的人单核细胞和内皮细胞中许多基因的诱导型表达。在这项研究中，我们研究了提高细胞内cAMP的药物抑制肿瘤坏死因子α（TNF α）、组织因子、内皮白细胞粘附分子-1和血管细胞粘附分子-1基因表达的分子机制。毛喉素和双丁酰cAMP通过独立机制升高细胞内cAMP，在转录水平抑制TNF α和组织因子表达。瞬时转染的人单核细胞THP-1细胞和人脐静脉内皮细胞中NF-κ B依赖性基因表达的诱导被升高的cAMP和蛋白激酶A（PKA）催化亚基的过表达抑制。升高的cAMP不能阻止p50/p65和c-Rel/p65异二聚体的核转位，减少p65的核转位，或显著改变TNF α诱导的p65磷酸化。功能研究表明，p65对含有多聚化κ B位点的质粒的转录激活被升高cAMP的试剂和PKA催化亚基的过表达抑制。这项研究表明，PKA的激活通过抑制NF-κ B介导的转录减少单核细胞和内皮细胞中一组不同基因的诱导。
The NF-kappa B/Rel family of transcription factors regulates the inducible expression of many genes in activated human monocytes and endothelial cells. In this study, we examined the molecular mechanism by which agents that elevate intracellular cAMP inhibit the expression of the tumor necrosis factor alpha (TNF alpha), tissue factor, endothelial leukocyte adhesion molecule-1, and vascular cell adhesion molecule-1 genes. Both forskolin and dibutyryl cAMP, which elevate intracellular cAMP by independent mechanisms, inhibited TNF alpha and tissue factor expression at the level of transcription. Induction of NF-kappa B-dependent gene expression in transiently transfected human monocytic THP-1 cells and human umbilical vein endothelial cells was inhibited by elevated cAMP and by overexpression of the catalytic subunit of protein kinase A (PKA). Elevated cAMP did not prevent nuclear translocation of p50/p65 and c-Rel/p65 heterodimers, decrease nuclear translocation of p65, or significantly modify TNF alpha-induced phosphorylation of p65. Functional studies demonstrated that transcriptional activation of a plasmid containing multimerized kappa B sites by p65 was inhibited by agents that elevate cAMP and by overexpression of the catalytic subunit of PKA. This study indicates that activation of PKA reduces the induction of a distinct set of genes in monocytes and endothelial cells by inhibiting NF-kappa B-mediated transcription.