IL-18 gene therapy develops Th1-type immune responses in Leishmania major-infected BALB/c mice: is the effect mediated by the CpG signaling TLR9?
IL-18 gene therapy develops Th1-type immune responses in Leishmania major-infected BALB/c mice: is the effect mediated by the CpG signaling TLR9?
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DOI：
10.1038/sj.gt.3302240
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发表时间：
2004-06-01
期刊：
影响因子：
5.1
通讯作者：
Himeno, K
中科院分区：
文献类型：
--
作者：
Li, Y;Ishii, K;Himeno, K
IL-18根据细胞因子微环境调节Th1或Th2反应。在BALB/c易感小鼠中，单独给药重组IL-18 （IL-18）不会促进Th1反应，但会诱导Th2反应，并加重利什曼原虫大感染。本研究在L. major感染BALB/c小鼠后，每周用表达il -18的质粒用基因枪处理。该基因治疗通过诱导IL-12 p40的表达改善了发病过程，并优先诱导Th1反应，而rIL-18治疗则没有。值得注意的是，尽管单独使用rIL-18或单独使用质粒载体并不影响易感性，但同时使用空质粒载体il -18使BALB/c小鼠对感染产生抗性。发现该载体与rIL-18的协同作用依赖于CpG基序，CpG基序通过toll样受体（TLR） 9连接增强APCs的促炎细胞因子，特别是IL-12的表达。在与il -18共给药的情况下，CpG被破坏的甲基化质粒载体不能再阻止疾病的发展。综上所述，IL-18基因治疗可在L. major感染的BALB/c小鼠中产生th1型保护性免疫，而不需要外源IL-12，可能是通过CpG-TLR9信号通路。
IL-18 regulates either Th1 or Th2 responses depending on the cytokine microenvironment. Administration of recombinant IL-18 (rIL-18) alone does not promote Th1 response, but rather induces Th2 response and exacerbates Leishmania major infection in susceptible BALB/c mice. Here, we treated BALB/c mice with an IL-18-expressing plasmid by using a gene gun weekly after L. major infection. This gene therapy resulted in improved pathogenic process and preferential induction of Th1 responses by inducing the expression of IL-12 p40, but treatment with rIL-18 did not. Notably, simultaneous administration of rIL-18 with an empty plasmid vector rendered BALB/c mice resistant to the infection, despite the fact that treatment with either rIL-18 alone or the plasmid vector alone did not influence the susceptibility. The synergistic role of the vector with rIL-18 was found to depend on CpG motifs, which enhanced expression of proinflammatory cytokines, especially IL-12, from APCs through Toll-like receptor (TLR) 9 ligation. Treatment with methylated plasmid vector in which CpG was disrupted could no longer prevent the disease development in coadministration with rIL-18. Taken together, IL-18 gene therapy was shown to develop Th1-type protective immunity in L. major-infected BALB/c mice without the requirement of exogenous IL-12, probably via CpG-TLR9 signaling pathway.