Mechanisms of Sequence-Dependent Activation in CpG DNA-Stimulated Human Cells

CpG DNA 刺激的人类细胞中序列依赖性激活的机制

• 批准号: 16590355
• 负责人: IHO Sumiko
• 金额: $ 2.3万
• 依托单位: University of Fukui
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590355/
• 关键词: CpG DNA; IFN-α; IRF-7; pDC; NF-κB; p38 MAPK; CXCL10; CCL3; IFN; IgE; 形質細胞様樹状細胞; INF-α; IRF; IP-10

The immunostimulatory activities of CpG DNA differ with their own sequences. Using polyG-flanked palindromic CpG DNA (unmodified), we examined the mechanisms through which CpG DNA activates plasmacytoid dendritic cells (pDC) in humans.In pDC, NF-κB family proteins p65 and p50 were constitutively activated. pDC also constitutively expressed IRF-7 and CCL3, and the expression of these genes seemed to be regulated by NF-κB. CpG DNA enhanced the NF-κB p65/p50 activity, which collaborated with p38 MAPK downstream of TLR9 to up-regulate the expressions of IRF-7, CXCL10, and CCL3 in a manner independent of type I IFN signaling. Following the simulation with CpG DNA, IRF-7, both constitutively and newly expressed, moved to the nuclei in a manner independent of NF-κB/p38 MAPK to transcribe the gene for IFN-α. IFN-α, secreted once, returned to pDC and upregulated the expression of IRF-7 independently of NF-κB/p38 MAPK. CpG DNA suppressed IgE production via the activation of pDC.These findings suggest that (1) there are two pathways in CpG DNA-stimulated human pDC : one dependent on NF-κB and the other independent of NF-κB. The former induces IRF-7, CXCL10, and CCL3, whereas the latter is involved in the activation of IRF-7. (2) IRF-7 induced independently of type I IFN signaling appears to be important for the expression of IFN-α, as the inhibition of NF-κB pathway abrogated the expression of IFN-α. (3) Activation of pDC by CpG DNA would be a promising strategy for inhibiting allergy, as CpG DNA-stimulated pDC suppressed IgE production.

CpG DNA的免疫刺激活性因其序列不同而不同。我们利用多聚G侧翼回文CpG DNA（未修饰）研究了CpG DNA激活人浆细胞样树突状细胞（pDC）的机制，在pDC中，NF-κB家族蛋白p65和p50被组成性激活。pDC还组成性表达IRF-7和CCL 3，这些基因的表达似乎受NF-κB的调节。CpG DNA增强NF-κB p65/p50活性，与TLR 9下游的p38 MAPK协同作用，以不依赖于I型IFN信号的方式上调IRF-7、CXCL 10和CCL 3的表达。在用CpG DNA模拟后，组成型和新表达的IRF-7以不依赖于NF-κB/p38 MAPK的方式移动到细胞核以转录IFN-α基因。IFN-α分泌一次后，返回pDC并上调IRF-7的表达，而不依赖于NF-κB/p38 MAPK。这些结果提示：（1）CpG DNA刺激的pDC存在两条途径：一条依赖于NF-κB，另一条不依赖于NF-κB。前者诱导IRF-7、CXCL 10和CCL 3，而后者参与IRF-7的激活。(2)独立于I型IFN信号传导诱导的IRF-7似乎对IFN-α的表达很重要，因为NF-κB途径的抑制消除了IFN-α的表达。(3)通过CpG DNA激活pDC将是抑制变态反应的有希望的策略，因为CpG DNA刺激的pDC抑制IgE产生。

项目成果

Activation Mechanism of IRF-7 in plasmacytoid dendritic cells (in Japanese)

浆细胞样树突状细胞中IRF-7的激活机制（日文）

• 发表时间: 2006
• 期刊: Proceedings for priority research of Fukui University (Fukui-daigaku Jyutenn-kennkyu Seika-shu) (in press)
• 作者: Ogasawara;N.;Tsukamoto;T.;Mizoshita;T.;Inada;K.;Cao;X.;Takenaka;Y.;Joh;T.;Tatematsu;M.;Sumiko Iho
• 通讯作者: Sumiko Iho

喫煙による白血球増加とサイトカイン

吸烟引起的白细胞增多和细胞因子

• 发表时间: 2005
• 期刊: Life Support and Anesthesia 12
• 作者: Ogawa;M. et al.;Kumanogo A.et al.;伊保 澄子
• 通讯作者: 伊保 澄子

CpG DNAによるplasmacytoid樹状細胞の活性化

CpG DNA 激活浆细胞样树突状细胞

• 发表时间: 2004
• 期刊: 臨床免疫 41・1
• 作者: Suzuki;T. et al.;Hidetomo Kobayashi;Ono et al.;Tsukamoto et al.;高氏留美子
• 通讯作者: 高氏留美子

PolyG-flanked palindromic CpG DNA activates STAT1 and NF-κB through the p38 MAPK pathway to induce autocrine IFN-α/β-independent production of IFN-α, P-10, and MIP-1α in human plasmacytoid dendritic cells.

PolyG 侧翼回文 CpG DNA 通过 p38 MAPK 途径激活 STAT1 和 NF-κB，诱导人浆细胞样树突状细胞中不依赖自分泌 IFN-α/β 产生 IFN-α、P-10 和 MIP-1α。

• 发表时间: 2004
• 期刊: J.Endotoxin Res. 10
• 作者: Osawa;Y.
• 通讯作者: Y.

福井大学重点研究「競争的配分経費」形質細胞様樹状細胞におけるInterferon Regulatory Factor-7活性化機構の解析

福井大学优先研究“资金竞争分配”浆细胞样树突状细胞中干扰素调节因子7激活机制分析

• 发表时间: 2006
• 期刊: 福井大学重点研究成果集2005 (In press)
• 作者: Kato;S.;Tsukamoto;T.;Mizoshita;T.;Tanaka;H.;Kumagai;T.;Ota;H.;Katsuyama;T.;Asaka;M.;Tatematsu;M.;Sawada.K.et al.;伊保澄子
• 通讯作者: 伊保澄子