The newly identified CpG-N ODN208 protects mice from challenge with CpG-S ODN by decreasing TNF-α release

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• 作者：Liangxi Wang ; Weiwei Jiang ; Guofu Ding ; Hongwei Cao ; Yongling Lu ; Ping Luo ; Hong Zhou ; Jiang Zheng
• 关键词：Sepsis ; CpG-N ODN208 ; CpG-S ODN ; TNF-α ; TLR9
• 刊名：International Immunopharmacology
• 出版年：2007
• 出版时间：May 2007
• 年：2007
• 卷：7
• 期：5
• 页码：646-655
• 全文大小：1228 K

文摘

Administration of an excess of oligodeoxynucleotides containing immunostimulatory CpG motifs (CpG-S ODNs) may induce systemic inflammatory response syndrome (SIRS) and sepsis. Therefore, it is important to develop neutralizing CpG ODNs (CpG-N ODNs), which can be used to reduce the release of cytokines induced by the presence of CpG-S ODNs. In the present study, CpG-N ODN208 (5′-TGCCGCGGCAGA-3′), a neutralizing twelve-oligodeoxynucleotide molecule recently identified in our laboratory, inhibited TNF-α release from human peripheral blood mononuclear cells (hPBMCs) and murine RAW264.7 cells induced by CpG-S ODN exposure in a dose- and time-dependent manner. Flow cytometry revealed that CpG-N ODN208 decreased cell-surface binding and internalization of 6-FAM-CpG-S ODN. However, the decreased cell-surface binding and internalization of CpG-S ODN could not completely account for the decreased TNF-α release. RT-PCR experiments revealed that CpG-N ODN treatment could down-regulate the CpG-S ODN-induced upregulation of Toll-like receptor 9 (TLR9) mRNA expression. This finding suggested that the decreased cytokine release following CpG-N ODN treatment might be related to decreased TLR9 mRNA expression. In in vivo experiments, no protection was found when the ratio of CpG-N ODN to CpG-S ODN delivered to mice was 3:1. However, at a 5:1 ratio, CpG-N ODN208 could protect mice from an ordinarily lethal dose of CpG-S ODN. Furthermore, we found that CpG-N ODN208 treatment decreased serum TNF-α levels in mice injected with sublethal doses of CpG-S ODN whether the CpG-N ODN208 was added prior to or concurrent with the CpG-S ODN. Our results demonstrated that CpG-N ODN-mediated protection against a lethal challenge by CpG-S ODN was associated with the reduction of TNF-α release.