Department of Biochemistry and Molecular Biology, Aging-Associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu, Republic of Korea.
Oncol Rep. 2012 Apr;27(4):1213-8. doi: 10.3892/or.2011.1579. Epub 2011 Dec 6.
Synthetic oligodeoxynucleotides (ODNs) with the CpG-motifs are recognized by toll-like receptor 9 (TLR9), which elicits an immune response. Serum starvation of Raw264.7 cells increased tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression. However, treatment with CpG ODN reduced TRAIL expression as well as apoptosis by serum starvation. In serum starved cells, TLR9 inhibitors recovered the decreasing TRAIL expression and sub-G1 accumulation by CpG ODN. CpG ODN-regulated anti-apoptotic signals which were dependent on the Akt-FoxO3a signaling pathway. CpG ODNs activated Akt and inactivated FoxO3a in serum starved cells. Knockdown of FoxO3a by siRNA decreased TRAIL expression and apoptosis in serum-starved cells. In contrast, FoxO3a overexpression increased apoptosis by serum starvation, and CpG ODNs blocked these effects through TRAIL expression. LY294002, a PI3K-Akt inhibitor, blocked the CpG ODN effect of TRAIL expression and the sub-G1 population in serum starved cells. In contrast, overexpression of wild-type Akt reduced additional sub-G1 cells both in non-CpG ODN- and CpG ODN-treated cells. Taken together, these results demonstrate the involvement of Akt-FoxO3a signaling in TLR9-mediated downregulation of TRAIL and anti-apoptotic signals.
合成寡脱氧核苷酸（ODNs）与 CpG 基序被 Toll 样受体 9（TLR9）识别，从而引发免疫反应。Raw264.7 细胞的血清饥饿会增加肿瘤坏死因子相关凋亡诱导配体（TRAIL）的表达。然而，CpG ODN 的处理降低了 TRAIL 的表达以及血清饥饿引起的细胞凋亡。在血清饥饿的细胞中，TLR9 抑制剂恢复了 CpG ODN 引起的 TRAIL 表达和亚 G1 积累的减少。CpG ODN 调节的抗凋亡信号依赖于 Akt-FoxO3a 信号通路。CpG ODN 在血清饥饿的细胞中激活 Akt 并失活 FoxO3a。FoxO3a 的 siRNA 敲低降低了血清饥饿细胞中的 TRAIL 表达和凋亡。相反，FoxO3a 的过表达增加了血清饥饿引起的凋亡，CpG ODN 通过 TRAIL 表达阻断了这些作用。LY294002，一种 PI3K-Akt 抑制剂，阻断了 CpG ODN 对 TRAIL 表达和血清饥饿细胞中亚 G1 群体的作用。相反，野生型 Akt 的过表达增加了非 CpG ODN 和 CpG ODN 处理的细胞中额外的亚 G1 细胞。总之，这些结果表明 Akt-FoxO3a 信号通路参与了 TLR9 介导的 TRAIL 和抗凋亡信号的下调。
