Evaluation of proinflammatory cytokine production induced by linear and branched polyethylenimine/plasmid DNA complexes in mice
Evaluation of proinflammatory cytokine production induced by linear and branched polyethylenimine/plasmid DNA complexes in mice
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DOI：
10.1124/jpet.105.100669
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发表时间：
2006-06-01
影响因子：
3.5
通讯作者：
Hashida, Mitsuru
中科院分区：
文献类型：
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作者：
Kawakami, Shigeru;Ito, Yoshitaka;Hashida, Mitsuru
本研究的目的是评价线性和支链聚乙烯亚胺(PEI)/质粒DNA （pDNA）复合物（polyplex）诱导的细胞因子反应与PEI的氮和DNA磷酸比（N/P比）、pDNA的剂量、PEI的结构和分子量的关系，这些因素对PEI复合物的转染效果有重要影响。作为对照，选择体内转染效率高的N-[1-（2,3-二聚氧基）丙基]- N， N， N， N-三甲基氯化铵/胆固醇脂质体/pDNA复合物（脂质体）。无论N/P比、pDNA剂量或PEI的结构和分子量如何，注射polyplex后，促炎细胞因子如肿瘤坏死因子(TNF)- α的浓度都远低于lipoplex，尽管这些因素会影响体内转染效果。我们证明了活化的核因子- κ B的数量，它对细胞因子的产生有很大的贡献，与对照（未处理）水平相当，明显低于脂质体获得的水平。尽管在给予线性PEI复合物后，促炎细胞因子（tnf - α、干扰素- γ和白细胞介素-12）的产生减少，但血清丙氨酸转氨酶水平却以剂量依赖的方式被pDNA显著提高，这表明这种肝损伤不是由促炎细胞因子引起的。
The purpose of this study was to evaluate the cytokine response induced by linear and branched polyethylenimine (PEI)/plasmid DNA (pDNA) complex (polyplex) in relation to the ratio of PEI nitrogen and DNA phosphate (N/P ratio) of the polyplex, dose of pDNA, and structure and molecular weight of PEI, which are important for transfection efficacy of PEI polyplex. As a control, a N-[1-(2,3-dioleyloxy)propyl]-n,n,n-trimethylammonium chloride/cholesterol liposome/pDNA complex (lipoplex) was selected for its high transfection efficacy in vivo. The concentration of proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha were much lower after the administration of polyplex than lipoplex irrespective of the N/P ratio, dose of pDNA, or structure and molecular weight of PEI, although these factors affected the transfection efficacy in vivo. We demonstrated that the amount of activated nuclear factor-kappa B, which contributes substantially to the production of cytokines, was comparable with the control (no treatment) level, and significantly less than that obtained with lipoplex. Although the production of proinflammatory cytokines (TNF-alpha, interferon-gamma, and interleukin-12) was reduced on the administration of the linear PEI polyplex, serum alanine aminotransferase levels were significantly enhanced by pDNA in a dose-dependent manner, suggesting that such hepatic damage is not induced by proinflammatory cytokines.