The promotion of type 1 T helper cell responses to cationic polymers in vivo via toll-like receptor-4 mediated IL-12 secretion
The promotion of type 1 T helper cell responses to cationic polymers in vivo via toll-like receptor-4 mediated IL-12 secretion
复制标题
通过 Toll 样受体 4 介导的 IL-12 分泌，促进 1 型 T 辅助细胞对体内阳离子聚合物的反应。
DOI：
10.1016/j.biomaterials.2010.07.056
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发表时间：
2010-11-01
期刊：
影响因子：
14
通讯作者：
Zhang, Junfeng
中科院分区：
文献类型：
--
作者：
Chen, Huan;Li, Pei;Zhang, Junfeng
阳离子聚合物作为核酸药物载体在实验和临床研究中有着广泛的应用。然而，它们与免疫系统的相互作用很少被研究。在本研究中，阳离子聚合物包括PEI、聚赖氨酸、阳离子葡聚糖和阳离子明胶表现出强烈的刺激Th 1反应，其特征在于诱导CD 4（+）T细胞增殖和Th 1相关细胞因子的分泌。在巨噬细胞上进行的实验表明，阳离子聚合物特异性地刺激巨噬细胞分泌IL-12，IL-12是主要的Th 1诱导细胞因子之一。MyD 88抑制剂显著降低阳离子聚合物诱导的IL-12表达，提示这种刺激作用主要通过TLR途径介导。此外，阳离子聚合物可强烈抑制LPS诱导的巨噬细胞中TNF-α分泌。这一结果提示阳离子聚合物可能通过LPS的受体TLR-4与巨噬细胞相互作用。以下使用TLR-4抗体抑制由阳离子聚合物刺激的IL-12表达的试验证明刺激主要由TLR-4介导。研究表明，阳离子聚合物的增产效果与其阳离子度有关，用阴离子聚合物中和阳离子聚合物可完全消除其增产效果。聚合物的分子量也影响其刺激能力，分子量越大刺激能力越强。结论：阳离子聚合物可通过TLR-4介导的IL-12分泌促进体内Th 1应答，其分子量和阳离子化程度决定了聚合物的刺激能力。(C)2010爱思唯尔有限公司版权所有。
Cationic polymers with nucleic acid drug delivery ability are widely used in experimental and clinical studies. However, their interactions with the immune systems are rarely studied. In the present study, cationic polymers including PEI, polylysine, cationic dextran and cationic gelatin exhibited strong stimulation on Th1 response which was characterized by the induction of the proliferation of CD4(+) T cells and the secretion of Th1 related cytokines. Experiments performed on macrophages demonstrated that cationic polymers specifically stimulated the macrophage to secrete IL-12 which is one of the main Th1-inducing cytokines. The result that MyD88 inhibitor remarkably reduced the IL-12 expression induced by cationic polymers suggested that this stimulation was mainly mediated by toll-like receptor (TLR) pathway. Additionally, cationic polymers could strongly inhibit LPS-induced TNF-alpha secretion in macrophages. This result implied that cationic polymers may interact with macrophages through TLR-4 which is the receptor of LPS. The following test of inhibiting IL-12 expression stimulated by cationic polymers using TLR-4 antibody proved that the stimulation was mainly mediated by TLR-4. Data in the present study demonstrated that the stimulation ability of cationic polymer was related with its cationic degree and neutralizing cationic polymer with anionic polymer completely abrogated the stimulation effect. The molecular weight of the polymers also influenced their stimulation ability, larger molecular means stronger stimulation ability. In conclusion, the present study revealed that cationic polymers could promote Th1 responses in vivo via TLR-4 mediated IL-12 secretion and the molecular weight and cationic degree of the polymers determined the stimulation ability. (C) 2010 Elsevier Ltd. All rights reserved.