Regulation of allergic airway inflammation through Toll-like receptor 4-mediated modification of mast cell function
Regulation of allergic airway inflammation through Toll-like receptor 4-mediated modification of mast cell function
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DOI：
10.1073/pnas.0510685103
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发表时间：
2006-02-14
影响因子：
11.1
通讯作者：
Nakayama, T
中科院分区：
文献类型：
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作者：
Nigo, YI;Yamashita, M;Nakayama, T
在小鼠实验性哮喘模型中，给予细菌脂多糖（LIPS），特别是低剂量，可增强卵清蛋白（OVA）诱导的嗜酸性气道炎症水平。为了阐明LPS作用的细胞和分子基础，我们证明了在野生型小鼠中给予LPS显著增加了OVA诱导的肺嗜酸性粒细胞炎症，而在肥大细胞缺陷型小鼠或Toll样受体（TLR）4缺陷型小鼠中未观察到这种增加。从野生型小鼠连续转移骨髓来源的肥大细胞（BMMC），而不是从TLR 4缺陷小鼠，恢复肥大细胞缺陷小鼠增加的嗜酸性粒细胞炎症。在体外用LPS预处理的野生型BMMC也重建嗜酸性粒细胞炎症。此外，体外分析显示，用LPS处理BMMC导致NF-κ B活化，持续上调GATA 1和-2表达，并增加产生IL-5和-13的能力。在用LIPS和IgE/Ag共刺激后，在LIPS处理的BMMC中检测到IL-5和IL-13以及Eotaxin 2的表达的急剧增加。在MC 9肥大细胞中，GATA 1而非GATA 2的过表达导致IL-4、IL-5和IL-13的转录活性增加。此外，通过引入GATA 1的小干扰RNA，BMMC中Th 2细胞因子的转录水平降低。因此，肥大细胞似乎控制过敏性气道炎症后，通过TLR 4介导的诱导GATA 1和随后的增加，在Th 2细胞因子的生产激活和调制。
In a mouse experimental asthma model, the administration of bacterial lipopolysaccharide (LIPS), particularly at low doses, enhances the levels of ovalbumin (OVA)-induced eosinophilic airway inflammation. In an effort to clarify the cellular and molecular basis for the LPS effect, we demonstrate that the OVA-induced eosinophilic inflammation in the lung is dramatically increased by the administration of LPS in wild-type mice, whereas such increase was not observed in mast-cell-deficient mice or Toll-like receptor (TLR)4-deficient mice. Adoptive transfer of bone-marrow-derived mast cells (BMMCs) from wild-type, but not from TLR4-deficient, mice restored the increased eosinophilic inflammation in mast-cell-deficient mice. Wild-type BMMCs pretreated with LPS in vitro also reconstituted the eosinophilic inflammation. Moreover, in vitro analysis revealed that the treatment of BMMCs with LPS resulted in NF-kappa B activation, sustained up-regulation of GATA1 and -2 expression, and increased the capability to produce IL-5 and -13. Dramatic increases in the expression of IL-5 and -13 and Eotaxin 2 were detected in LIPS-treated BMMCs after costimulation with LIPS and IgE/Ag. Overexpression of GATA1, but not GATA2, in MC9 mast cells resulted in increased transcriptional activity of IL-4, -5, and -13. Furthermore, the levels of transcription of Th2 cytokines in BMMCs were decreased by the introduction of small interfering RNA for GATA1. Thus, mast cells appear to control allergic airway inflammation after their activation and modulation through TLR4-mediated induction of GATA1 and subsequent increase in Th2 cytokine production.