Toll-like receptor agonists induce apoptosis in mouse B-cell lymphoma cells by altering NF-κB activation.
Toll-like receptor agonists induce apoptosis in mouse B-cell lymphoma cells by altering NF-κB activation.
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DOI：
10.1038/cmi.2013.14
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发表时间：
2013-07
影响因子：
24.1
通讯作者：
中科院分区：
文献类型：
--
作者：
toll样受体9 （TLR9）识别含有未甲基化胞基鸟嘌呤（CpG）序列的微生物DNA，诱导先天免疫反应，促进抗原特异性适应性免疫。最近的研究报道，TLR9配体除了刺激先天免疫外，还能诱导表达TLR9的癌细胞凋亡。为了了解tlr9诱导细胞凋亡的机制，我们比较了含有寡脱氧核苷酸的CpG （CpG ODN）对小鼠淋巴瘤B细胞株CH27和小鼠脾B细胞的影响。CpG ODN抑制CH27淋巴瘤B细胞的组成性增殖并诱导凋亡，而CpG ODN处理的原代B细胞被刺激增殖并从自发凋亡中拯救出来。在淋巴瘤B细胞中，凋亡的诱导需要odn中的CpG基序和TLR9的表达。随着淋巴瘤B细胞的凋亡，Bcl-xl的表达减少，Fas及Fas配体的表达增加。Fas配体中和抗体处理可抑制cpgodn诱导的细胞凋亡。CpG ODN在组成性表达高水平c-Myc的淋巴瘤B细胞中触发NF-κB的短暂激活，同时诱导原代B细胞中NF-κB激活和c-Myc表达的持续增加。NF-κB抑制剂对CH27淋巴瘤B细胞增殖有抑制作用。我们的数据表明，淋巴瘤和原代B细胞对CpG ODN的不同反应是NF-κB活化差异的结果。在CpG odn处理的淋巴瘤B细胞中，NF-κB活化受损改变了NF-κB和c-Myc之间的平衡，诱导Fas/Fas配体依赖性凋亡。
Toll-like receptor 9 (TLR9) recognizes microbial DNA containing unmethylated cytosyl guanosyl (CpG) sequences, induces innate immune responses, and facilitates antigen-specific adaptive immunity. Recent studies reported that in addition to stimulating innate immunity, TLR9 ligands induce apoptosis in TLR9 expressing cancer cells. To understand the mechanism of TLR9-induced apoptosis, we compared the effects of CpG containing oligodeoxynucleotides (CpG ODN) on a mouse lymphoma B cell line CH27 with mouse splenic B cells. CpG ODN inhibited constitutive proliferation and induced apoptosis of CH27 lymphoma B cells, in contrast to CpG ODN-treated primary B cells that were stimulated to proliferate and rescued from spontaneous apoptosis. The induction of apoptosis required CpG motif in ODNs and expression of TLR9 in lymphoma B cells. Accompanying the apoptosis of the lymphoma B cells, there was a decrease in Bcl-xl and an increase in the expression of Fas and Fas ligand. The treatment of Fas ligand neutralizing antibody inhibited CpG ODN-induced apoptosis. CpG ODN triggered a transient activation of NF-κB in the lymphoma B cells that constitutively expressed a high level of c-Myc, while it induced sustained increases in NF-κB activation and c-Myc expression in the primary B cells. Furthermore, NF-κB inhibitor inhibited the proliferation of CH27 lymphoma B cells. Our data suggest that the differential responses of lymphoma and primary B cells to CpG ODN are the result of differences in NF-κB activation. The impaired NF-κB activation in CpG ODN-treated lymphoma B cells alters the balance between NF-κB and c-Myc, inducing Fas/Fas ligand-dependent apoptosis.
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