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首页> 美国卫生研究院文献>Clinical and Experimental Immunology >Modulation of proinflammatory cytokine production in tumour necrosis factor-alpha (TNF-α)-transgenic mice by treatment with cells engineered to secrete IL-4 IL-10 or IL-13
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Modulation of proinflammatory cytokine production in tumour necrosis factor-alpha (TNF-α)-transgenic mice by treatment with cells engineered to secrete IL-4 IL-10 or IL-13

机译：通过工程改造分泌IL-4IL-10或IL-13的细胞处理来调节肿瘤坏死因子-α（TNF-α）转基因小鼠中促炎细胞因子的产生

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TNF-α is one of the major proinflammatory cytokines involved in the pathogenesis of chronic inflammatory joint disease, in human rheumatoid arthritis as well as in murine models of this disease. It was previously described that a highly destructive chronic spontaneous inflammatory arthritis develops in mice expressing a human TNF-α transgene modified with the 3′ untranslated region of β-globin. The present study investigates in this mouse model the effects of the anti-inflammatory cytokines IL-4, IL-10 and IL-13 administered in vivo on proinflammatory cytokine expression. Groups of TNF-α-transgenic mice were engrafted with xenogeneic transfected Chinese hamster ovary (CHO) fibroblasts secreting murine IL-4, IL-10 or IL-13. In vivo treatments consisted of 3 or 4 weekly engraftments, starting when the mice were 4 weeks old. Control groups of transgenic mice were engrafted with β-galactosidase gene-transfected CHO cells or injected with medium. A significant decreased expression of TNF-α transgene, endogenous mouse TNF-α and IL-1 mRNA was observed in splenocytes of mice treated for 3 or 4 weeks with CHO/IL-4 and CHO/IL-13, and, to a lesser extent, with CHO/IL-10, compared with controls. Finally, attenuation of histological scores of arthritides was statistically significant only in the group of CHO/IL-4-treated mice after 3 weeks of treatment (P < 0.05), and was not significant in any other group. These results show that IL-4, IL-10 or IL-13, administered by gene therapy, can decrease the mRNA steady state levels of both endogenous and transgenic cytokines in human TNF-α transgenic mice. In addition, IL-4 can slightly attenuate the development of arthritides in this model.
机译：TNF-α是参与慢性炎性关节疾病，人类风湿性关节炎以及该疾病的小鼠模型的发病机理的主要促炎细胞因子之一。先前已经描述了在表达被β-珠蛋白的3'非翻译区修饰的人TNF-α转基因的小鼠中发展出高度破坏性的慢性自发性炎性关节炎。本研究在该小鼠模型中研究了体内施用的抗炎细胞因子IL-4，IL-10和IL-13对促炎细胞因子表达的影响。将每组TNF-α转基因小鼠植入异种转染的分泌鼠IL-4，IL-10或IL-13的中国仓鼠卵巢（CHO）成纤维细胞。从小鼠4周大时开始，体内治疗包括每周3或4次植入。将转基因小鼠的对照组移植有β-半乳糖苷酶基因转染的CHO细胞或注射培养基。在用CHO / IL-4和CHO / IL-13处理3或4周的小鼠脾细胞中观察到TNF-α转基因，内源性小鼠TNF-α和IL-1 mRNA的表达显着降低，并且在较小的程度上CHO / IL-10与对照相比的最大程度。最后，仅在CHO / IL-4处理的小鼠组中，治疗3周后关节炎的组织学评分衰减具有统计学意义（P <0.05），而在其他任何组中均无统计学意义。这些结果表明，通过基因疗法施用的IL-4，IL-10或IL-13可以降低人TNF-α转基因小鼠中内源性和转基因细胞因子的mRNA稳态水平。另外，在该模型中，IL-4可以稍微减弱关节炎的发展。

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