MDP 诱导的 TLR4 配体选择性耐受：NOD2 突变型克罗恩病患者的损害。

MDP-Induced selective tolerance to TLR4 ligands: impairment in NOD2 mutant Crohn's disease patients.

机构信息

Department of Immunology, Institut Rec & Hospital Sant Pau, Barcelona, Spain.

出版信息

Inflamm Bowel Dis. 2009 Nov;15(11):1686-96. doi: 10.1002/ibd.21013.

DOI:10.1002/ibd.21013

PMID:19572373

Abstract

BACKGROUND

Pathogen infection is a complex process in which several pathogen-recognition receptor (PRR) pathways are activated to induce proinflammatory mediators. The activation of multiple PRRs suggests an interaction between Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-like receptor (NOD) signaling pathways.

METHODS

To understand the modulation induced by NOD2 signals on successive responses to pathogen-associated molecular patterns (PAMPs), we examined how muramyl dipeptide (MDP) pretreatment reprograms the MDP+LPS (lipopolysaccharide) response of monocytes from human peripheral blood.

RESULTS

Preexposure to bacterial MDP components induced selective tolerance to a subsequent NOD2+TLR4 stimulation. MDP pretreatment inhibited the production of tumor necrosis factor alpha (TNFalpha) and interleuken 10 (IL10), whereas IL6 and IL8 remained unaffected. MDP-induced tolerance was independent of receptor downregulation but was associated with reduced levels of phosphorylated TAK1 and abrogated phosphorylation of the downstream MAPK.Since Nod2 mutations have been associated with susceptibility to develop Crohn's disease (CD), we compared the MDP-induced tolerance in healthy donors and CD patients with compound heterozygous Nod2 mutations (Mut-Nod2) expressing variant NOD2 proteins. MDP-induced tolerance in Mut-Nod2 patients reduced IL10 but not TNFalpha production. In contrast with healthy donors, a p38-independent TNFalpha production was observed during the kinetics of the MDP+LPS response in Mut-Nod2 patients.

CONCLUSIONS

Our findings suggest that the selective tolerance induced by MDP in healthy donors was related to the modulation of a convergent nub of NOD2 and TLR4 signaling pathways. This MDP-induced tolerance was impaired in Mut-Nod2 CD patients, resulting in a p38-independent TNFalpha production and an imbalance between pro- and antiinflammatory cytokines that could be partly responsible for the pathogenesis of CD.

摘要

背景

病原体感染是一个复杂的过程，其中几个病原体识别受体（PRR）途径被激活以诱导促炎介质。多种 PRR 的激活表明 Toll 样受体（TLR）和核苷酸结合寡聚化结构域样受体（NOD）信号通路之间存在相互作用。

方法

为了了解 NOD2 信号对病原体相关分子模式（PAMP）连续反应的诱导调节，我们研究了 NOD2 信号的激活如何重塑人外周血单核细胞对 muramyl dipeptide（MDP）+LPS（脂多糖）的反应。

结果

细菌 MDP 成分的预暴露诱导对随后的 NOD2+TLR4 刺激产生选择性耐受。MDP 预处理抑制肿瘤坏死因子-α（TNFα）和白细胞介素 10（IL10）的产生，而白细胞介素 6（IL6）和白细胞介素 8（IL8）不受影响。MDP 诱导的耐受与受体下调无关，但与磷酸化 TAK1 水平降低和下游 MAPK 磷酸化缺失有关。由于 Nod2 突变与易患克罗恩病（CD）有关，我们比较了健康供体和复合杂合 Nod2 突变（Mut-Nod2）的 CD 患者中 MDP 诱导的耐受性，这些患者表达变异的 NOD2 蛋白。Mut-Nod2 患者中 MDP 诱导的耐受性降低了 IL10 但不影响 TNFα的产生。与健康供体不同，在 Mut-Nod2 患者的 MDP+LPS 反应动力学中观察到 p38 非依赖性 TNFα的产生。