Genome-Wide Expression Profiling Identifies an Impairment of Negative Feedback Signals in the Crohn's Disease-Associated NOD2 Variant L1007fsinsC
Genome-Wide Expression Profiling Identifies an Impairment of Negative Feedback Signals in the Crohn's Disease-Associated NOD2 Variant L1007fsinsC
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DOI：
10.4049/jimmunol.1000085
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发表时间：
2011-04-01
影响因子：
4.4
通讯作者：
Rosenstiel, Philip
中科院分区：
文献类型：
--
作者：
Billmann-Born, Susanne;Till, Andreas;Rosenstiel, Philip
NOD2是细菌细胞壁成分muramyl二肽（MDP）的细胞内受体，NOD2的变异与屏障器官的慢性炎症性疾病（如克罗恩病、哮喘和特应性湿疹）有关。众所周知，NOD2的激活可诱导多种炎症和抗菌因子。定义NOD2激活下游细胞程序的确切转录特征和crohn相关变体L1007fsinsC的影响尚未确定。为了描述MDP诱导的激活程序，我们分析了表达NOD2（wt）或NOD2（L1007fsinsC）的等基因HEK293细胞对MDP刺激的转录反应。重要的是，在携带克克隆相关变异L1007fsinsC的细胞中可以观察到明显的功能丧失，而NOD2（wt）细胞对生长因子、趋化因子和几种NF-kappa B拮抗剂（如TNFAIP3 [A20]和IER3）表现出不同的调控。这种基因型依赖的调控模式在原代人骨髓单核细胞中得到证实。表征了TNFAIP3和IER3在NOD2信号传导背景下的影响，我们可以验证其作为NOD2诱导的NF-kappa B激活抑制剂的预测作用。我们发现IER3削弱NOD2（wt）对细菌细胞入侵的保护作用。这些结果进一步加深了我们对NOD2作为一线防御分子的理解，并强调了同时上调抗调节抗炎因子作为NOD2诱导细胞程序不可分割的一部分的重要性。由于L1007fsinsC变异体缺乏这些调节事件，可能对慢性炎症的诱导和延续起关键作用。免疫学杂志，2011,18(6):4027-4038。
NOD2 is an intracellular receptor for the bacterial cell wall component muramyl dipeptide (MDP), and variants of NOD2 are associated with chronic inflammatory diseases of barrier organs (e. g., Crohn's disease, asthma, and atopic eczema). It is known that activation of NOD2 induces a variety of inflammatory and antibacterial factors. The exact transcriptomal signatures that define the cellular programs downstream of NOD2 activation and the influence of the Crohn-associated variant L1007fsinsC are yet to be defined. To describe the MDP-induced activation program, we analyzed the transcriptomal reactions of isogenic HEK293 cells expressing NOD2(wt) or NOD2(L1007fsinsC) to stimulation with MDP. Importantly, a clear loss of function could be observed in the cells carrying the Crohn-associated variant L1007fsinsC, whereas the NOD2(wt) cells showed differential regulation of growth factors, chemokines, and several antagonists of NF-kappa B (e. g., TNFAIP3 [A20] and IER3). This genotype-dependent regulation pattern was confirmed in primary human myelomonocytic cells. The influence of TNFAIP3 and IER3 in the context of NOD2 signaling was characterized, and we could validate the predicted role as inhibitors of NOD2-induced NF-kappa B activation. We show that IER3 impairs the protective effect of NOD2(wt) against bacterial cytoinvasion. These results further our understanding of NOD2 as a first-line defense molecule and emphasize the importance of simultaneous upregulation of counter-regulatory anti-inflammatory factors as an integral part of the NOD2-induced cellular program. Lack of these regulatory events due to the L1007fsinsC variant may pivotally contribute to the induction and perpetuation of chronic inflammation. The Journal of Immunology, 2011, 186: 4027-4038.