Laboratory of Systems Mucosal Biomodulation, Department of Microbiology and Immunology and Medical Research Institute, Pusan National University School of Medicine, Yangsan 626-813, Korea.
Toxicol Sci. 2012 Jan;125(1):116-25. doi: 10.1093/toxsci/kfr270. Epub 2011 Oct 14.
Chronic exposure to gut bacteria and bacterial products including Nod2 ligands triggers homeostatic regulation in response to various mucosal insults. Activating transcription factor 3 (ATF3) is a negative regulator of proinflammatory cytokines via bacterial pattern recognition. On the assumption that ATF3 can be a critical modulator of epithelial inflammation, chronic stimulation of Nod2 was assessed for its effects on ATF3 and proinflammatory signals in response to mucosal ribotoxic insult, which is a critical etiological factor of human intestinal inflammatory disease. Muramyl dipeptide, the minimal moiety of bacterial peptidoglycan, is the Nod2 ligand, and pre-exposure to it enhanced ATF3 expression in ribotoxic stress-exposed human enterocytes. In terms of gene regulation, Nod2 preactivation potentiated ATF3 induction by enhancing stability of the ATF3 transcript, which was particularly linked to the regulation of the 3'-untranslated region of the human ATF3 gene. Moreover, chronic stimulation of Nod2 enhanced both the basal and the ribotoxic stress-stimulated cytoplasmic translocation of the HuR protein, which bound to and stabilized ATF3 messenger RNA (mRNA). Functionally, chronic stimulation of Nod2 also led to superinduction of proinflammatory chemokine genes by the mucoactive ribotoxic stress. However, the chemokine superinduction was not affected by ATF3 gene regulation although Nod2-triggered ATF3 had suppressive effects on the proinflammatory nuclear factor kappa B (NF-κB) signal. This paradoxical superinduction of chemokines was also mediated by enhanced mRNA stabilization by HuR protein in spite of ATF3-mediated suppression of NF-κB signal in human intestinal epithelial cells.
慢性暴露于肠道细菌和细菌产物，包括 Nod2 配体，会触发针对各种黏膜损伤的体内平衡调节。激活转录因子 3（ATF3）是通过细菌模式识别对促炎细胞因子的负调控因子。假设 ATF3 可以成为上皮炎症的关键调节剂，评估了 Nod2 的慢性刺激对黏膜核糖毒性损伤反应中的 ATF3 和促炎信号的影响，这是人类肠道炎症性疾病的一个关键病因。细菌肽聚糖的最小部分 muramyl dipeptide 是 Nod2 的配体，预先暴露于它会增强核糖毒性应激暴露的人肠细胞中 ATF3 的表达。在基因调节方面，Nod2 的预先激活通过增强 ATF3 转录本的稳定性来增强 ATF3 的诱导，这与人类 ATF3 基因 3'-非翻译区的调节特别相关。此外，Nod2 的慢性刺激增强了 HuR 蛋白的基础和核糖毒性应激刺激的细胞质易位，HuR 蛋白与 ATF3 信使 RNA（mRNA）结合并稳定其。从功能上讲，Nod2 的慢性刺激也导致了 mucoactive 核糖毒性应激引起的促炎趋化因子基因的超诱导。然而，尽管 Nod2 触发的 ATF3 对促炎核因子 kappa B（NF-κB）信号具有抑制作用，但趋化因子的超诱导不受 ATF3 基因调控的影响。尽管 ATF3 介导了 NF-κB 信号的抑制，但 HuR 蛋白增强 mRNA 稳定性也介导了这种趋化因子的悖论性超诱导，在人类肠道上皮细胞中。
