Mycobacterium paratuberculosis is recognized by Toll-like receptors and NOD2
Mycobacterium paratuberculosis is recognized by Toll-like receptors and NOD2
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DOI：
10.1189/jlb.0307147
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发表时间：
2007-10-01
影响因子：
5.5
通讯作者：
Netea, Mihai G.
中科院分区：
文献类型：
--
作者：
Ferwerda, Gerben;Kullberg, Bart Jan;Netea, Mihai G.
副结核分枝杆菌已被认为参与克罗恩病（CD）的发病机制。CD与细胞内病原体识别受体（PRR）核苷酸结合寡聚结构域2 （NOD2）突变的关联支持了微生物在CD中的重要性。本研究的目的是探讨PRR参与副结核分枝杆菌的识别。使用的方法包括体外刺激转染细胞系、小鼠巨噬细胞和人PBMC。副结核分枝杆菌主要刺激人TLR2 (hTLR2)-中国仓鼠卵巢（CHO）细胞，hTLR4-CHO细胞轻度刺激。与对照组相比，TLR2和TLR4敲除小鼠的巨噬细胞在副结核分枝杆菌刺激后产生的细胞因子较少。TLR4在人PBMC中的抑制作用仅在活的副结核分枝杆菌刺激后才会减少细胞因子的产生。tlr诱导的tnf - α、IL-1 β和IL-10的产生是通过MyD88介导的，而Toll-IL-1R结构域适配器诱导的ifn - β (TRIF)促进了IL-1 β的释放。hnod2 -人胚胎肾（HEK）细胞，而不是hNOD1-HEK细胞，对副结核分枝杆菌的刺激有反应。3020insC NOD2突变纯合个体的PBMC在副结核分枝杆菌刺激后显示出70%的缺陷细胞因子反应。这些结果表明，TLR2、TLR4和NOD2参与了先天免疫系统对副结核分枝杆菌的识别。
Mycobacterium paratuberculosis has been suggested to be involved in the pathogenesis of Crohn's disease (CD). The importance of microorganisms in CD is supported by the association of CD with mutations in the intracellular pathogen recognition receptor (PRR) nucleotide-binding oligomerization domain 2 (NOD2). The aim of this study is to investigate the PRR involved in the recognition of M. paratuberculosis. Methods used include in vitro stimulation of transfected cell lines, murine macrophages, and human PBMC. M. paratuberculosis stimulated human TLR2 (hTLR2)-Chinese hamster ovary (CHO) cells predominantly and hTLR4-CHO cells modestly. Macrophages from TLR2 and TLR4 knockout mice produced less cytokines compared with controls after stimulation with M. paratuberculosis. TLR4 inhibition in human PBMC reduced cytokine production only after stimulation with live M. paratuberculosis. TLR-induced TNF-alpha, IL-1 beta, and IL-10 production is mediated through MyD88, whereas Toll-IL-1R domain-containing adaptor inducing IFN-beta (TRIF) promoted the release of IL-1 beta. hNOD2-human embryo kidney (HEK) cells, but not hNOD1-HEK cells, responded to stimulation with M. paratuberculosis. PBMC of individuals homozygous for the 3020insC NOD2 mutation showed a 70% defective cytokine response after stimulation with M. paratuberculosis. These results demonstrate that TLR2, TLR4, and NOD2 are involved in the recognition of M. paratuberculosis by the innate immune system.