Negative regulation of Toll-like receptor signaling plays an essential role in homeostasis of the intestine.
Negative regulation of Toll-like receptor signaling plays an essential role in homeostasis of the intestine.
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DOI：
10.1002/eji.201040479
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发表时间：
2011-01
影响因子：
5.4
通讯作者：
Kobayashi, Koichi S.
中科院分区：
文献类型：
--
作者：
Biswas, Amlan;Wilmanski, Jeanette;Forsman, Huamei;Hrncir, Tomas;Hao, Liming;Tlaskalova-Hogenova, Helena;Kobayashi, Koichi S.
由于共生细菌和宿主粘膜免疫系统之间的平衡相互作用，健康的肠道具有受控的动态平衡的特征。人类和动物模型研究支持这一假设，即这种内稳态的破坏可能是炎症性肠病(IBD)发病机制的基础。然而，目前还不清楚肠道微生物区系如何刺激肠道粘膜免疫系统，以及这种激活是如何调节的。利用IL-10缺陷小鼠自发的共生细菌依赖性结肠炎模型，我们研究了Toll样受体(TLRs)在肠道内稳态中的作用及其负调控。除IL-10−/−MyD88−/−小鼠外，IL-10−/−TLR4−/−小鼠的结肠炎较IL-10−/−小鼠明显减轻，提示TLR4信号在诱导结肠炎中起重要作用。有趣的是，TLR信号的负调控因子IRAK-M的表达依赖于肠道共生菌群，因为IRAK-M的表达在重新衍生到无菌环境中的小鼠中降低，而将共生细菌引入无菌小鼠诱导了IRAK-M的表达。IL-10−/−IRAK-M−/−小鼠表现为结肠炎加重，炎性细胞因子基因表达增加。因此，本研究表明肠道微生物群通过TLRs刺激结肠性免疫系统，TLR信号的负调控在维持肠道内环境稳定中起重要作用。
A healthy intestinal tract is characterized by controlled homeostasis due to the balanced interaction between commensal bacteria and the host mucosal immune system. Human and animal model studies have supported the hypothesis that breakdown of this homeostasis may underlie the pathogenesis of inflammatory bowel diseases (IBDs). However it is not well understood how intestinal microflora stimulate the intestinal mucosal immune system and how such activation is regulated. Using a spontaneous, commensal bacteria-dependent colitis model in IL-10-deficient mice, we investigated the role of Toll-like receptors (TLRs) and their negative regulation in intestinal homeostasis. In addition to IL-10−/−MyD88−/− mice, IL-10−/−TLR4−/− mice exhibited reduced colitis compared to IL-10−/− mice, indicating that TLR4 signaling plays an important role in inducing colitis. Interestingly, the expression of IRAK-M, a negative regulator of TLR signaling, is dependent on intestinal commensal flora, as IRAK-M expression was reduced in mice re-derived into a germ-free environment, and introduction of commensal bacteria into germ-free mice induced IRAK-M expression. IL-10−/−IRAK-M−/− mice exhibited exacerbated colitis with increased inflammatory cytokine gene expression. Therefore, this study indicates that intestinal microflora stimulate the colitogenic immune system through TLRs and negative regulation of TLR signaling is essential in maintaining intestinal homeostasis.
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影响因子：
32.4
作者：
Kawai, T;Adachi, O;Akira, S
通讯作者：
Akira, S
DOI：
10.1111/j.1365-2672.1994.tb03443.x
发表时间：
1994-10-01
期刊：
JOURNAL OF APPLIED BACTERIOLOGY
影响因子：
--
作者：
GIBSON, GR;WANG, X
通讯作者：
WANG, X
影响因子：
30.5
作者：
Denning, Timothy L.;Wang, Yi-Chong;Pulendran, Bali
通讯作者：
Pulendran, Bali
影响因子：
56.9
作者：
Macpherson, AJ;Gatto, D;Zinkernagel, RM
通讯作者：
Zinkernagel, RM
影响因子：
9.8
作者：
Balaci, Lenuta;Spada, Maria Cristina;Pilia, Giuseppe
通讯作者：
Pilia, Giuseppe