Kwon Hyung-Joo, Lee Keun-Wook, Yu Sang Ho, Han Jung Ho, Kim Doo-Sik
Institute of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
Biochem Biophys Res Commun. 2003 Nov 7;311(1):129-38. doi: 10.1016/j.bbrc.2003.09.168.
Immunostimulatory activities of synthetic oligodeoxynucleotides containing CpG motifs (CpG-ODNs) have gained attention as potentially useful immunotherapeutics. However, CpG-ODNs induce harmful and lethal shock effects because they greatly enhance the sequence-dependent induction of tumor necrosis factor-alpha (TNF-alpha). We have shown that phosphorothioate-modified oligodeoxynucleotides (PS-ODNs) of the CpG-ODN 1826 stimulate TNF-alpha gene expression, TNF-alpha promoter activity, IkappaB degradation, and NF-kappaB activation at higher levels compared with its phosphodiester ODN (PO-ODN). In contrast to the effects of CpG-ODN 1826, PS-ODN of the CpG-ODN 2006 showed lower stimulatory activities than its PO-ODN. Using transient transfection, it was found that myeloid differentiation protein (MyD88) and tumor necrosis factor receptor-associated factor 6 are commonly required for activation of the TNF-alpha promoter by various CpG-ODNs with different potencies. These results strongly suggest a possibility to optimally activate the innate immune responses by modulating the potency of CpG-ODNs via sequence rearrangement and phosphorothioate backbone modification.
含有CpG基序的合成寡脱氧核苷酸（CpG-ODNs）的免疫刺激活性作为潜在有用的免疫疗法已受到关注。然而，CpG-ODNs会诱导有害和致命的休克效应，因为它们会极大地增强肿瘤坏死因子-α（TNF-α）的序列依赖性诱导。我们已经表明，与磷酸二酯寡脱氧核苷酸（PO-ODN）相比，CpG-ODN 1826的硫代磷酸酯修饰寡脱氧核苷酸（PS-ODNs）能更高水平地刺激TNF-α基因表达、TNF-α启动子活性、IkappaB降解和NF-kappaB激活。与CpG-ODN 1826的作用相反，CpG-ODN 2006的PS-ODN显示出比其PO-ODN更低的刺激活性。通过瞬时转染发现，髓样分化蛋白（MyD88）和肿瘤坏死因子受体相关因子6是各种具有不同效力的CpG-ODNs激活TNF-α启动子所共同需要的。这些结果强烈表明，通过序列重排和硫代磷酸酯主链修饰来调节CpG-ODNs的效力，有可能最佳地激活先天免疫反应。
