Dept. of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261.
Division of Rheumatology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224.
J Biol Chem. 2011 Oct 14;286(41):36076-36085. doi: 10.1074/jbc.M111.259549. Epub 2011 Aug 23.
Activation of the NF-κB signaling pathway is critical for leukocyte activation and development. Although previous studies suggested a role for the Akt kinase in coupling the T cell antigen receptor and CD28 to NF-κB activation in T cells, the nature of the role of Akt in this pathway is still unclear. Using a targeted gene profiling approach, we found that a subset of NF-κB-dependent genes required Akt for optimal up-regulation during T cell activation. The selective effects of Akt were manifest at the level of mRNA transcription and p65/RelA binding to upstream promoters and appear to be due to altered formation of the Carma1-Bcl10 complex. The proinflammatory cytokine TNF-α was found to be particularly sensitive to Akt inhibition or knockdown, including in primary human blood T cells and a murine model of rheumatoid arthritis. Our findings are consistent with a hierarchy in the expression of NF-κB-dependent genes, controlled by the strength and/or duration of NF-κB signaling. More broadly, our results suggest that defining the more graded effects of signaling, such as those demonstrated here for Akt and the NF-κB pathway, is important to understanding how cells can fine-tune signaling responses for optimal sensitivity and specificity.
NF-κB 信号通路的激活对于白细胞的激活和发育至关重要。虽然之前的研究表明 Akt 激酶在将 T 细胞抗原受体和 CD28 与 T 细胞中的 NF-κB 激活偶联方面起作用，但 Akt 在该途径中的作用性质仍不清楚。使用靶向基因谱分析方法，我们发现 NF-κB 依赖性基因的亚组在 T 细胞激活过程中需要 Akt 进行最佳上调。Akt 的选择性影响表现在 mRNA 转录水平和 p65/RelA 与上游启动子的结合上，并且似乎是由于 Carma1-Bcl10 复合物的形成发生改变。发现促炎细胞因子 TNF-α特别容易受到 Akt 抑制或敲低的影响，包括在原代人血液 T 细胞和类风湿关节炎的小鼠模型中。我们的研究结果与 NF-κB 依赖性基因的表达呈等级结构一致，受 NF-κB 信号的强度和/或持续时间控制。更广泛地说，我们的结果表明，定义信号的更分级效应，例如这里针对 Akt 和 NF-κB 途径所示的效应，对于理解细胞如何微调信号反应以获得最佳的灵敏度和特异性非常重要。
