Toll 样受体 4 和 Notch1 通路之间的串扰增强了狭窄人主动脉瓣间质细胞的炎症反应。
Cross-talk between the Toll-like receptor 4 and Notch1 pathways augments the inflammatory response in the interstitial cells of stenotic human aortic valves.
机构信息
Department of Surgery, University of Colorado Denver, Aurora, CO, USA.
出版信息
Circulation. 2012 Sep 11;126(11 Suppl 1):S222-30. doi: 10.1161/CIRCULATIONAHA.111.083675.
BACKGROUND AND PURPOSE
Calcific aortic stenosis is a chronic inflammatory disease, and aortic valve interstitial cells (AVIC) play an important role in valvular inflammation. Whereas AVIC from stenotic aortic valves exhibit an augmented response to Toll-like receptor 4 (TLR4) stimulation, the underlying mechanism is unclear. This study tested the hypothesis that an excessive cross-talk between the TLR4 and Notch1 pathways is responsible for augmentation of the inflammatory response to lipopolysaccharide (LPS) in AVIC of stenotic valves.
METHODS AND RESULTS
Human AVIC were isolated from normal and stenotic leaflets. Nuclear factor kappa-B (NF-κB) activation and production of interleukin-8, monocyte chemoattactrant protein-1, and intercellular adhesion molecule-1 were analyzed after treatment with LPS. The role of Notch1 in the inflammatory response was determined using inhibitor, siRNA, and specific ligand. Cells from diseased valves produced greater levels of chemokines and intercellular adhesion molecule-1 that are associated with enhanced NF-κB activation. Interestingly, diseased cells exhibited augmented Jagged1 release and Notch1 activation after TLR4 stimulation. Inhibition and silencing of Notch1 each resulted in greater suppression of the TLR4-induced inflammatory response in diseased cells. Conversely, activation of Notch1 with a specific ligand, Jagged1, enhanced the LPS-induced inflammatory response in normal AVIC. Further, Notch1 intracellular domain was coimmunoprecipited with the inhibitor of NF-κB kinase after LPS stimulation, and inhibition of Notch1 abrogated the difference in the level of NF-κB activation between diseased and normal cells.
CONCLUSION
Notch1 enhances the inflammatory response to TLR4 stimulation in human AVIC through modulating NF-κB activation. Excessive cross-talk between the TLR4 and Notch1 pathways is responsible for augmentation of the TLR4 response in AVIC of stenotic valves.
背景与目的
钙化性主动脉瓣狭窄是一种慢性炎症性疾病，主动脉瓣间质细胞（AVIC）在瓣膜炎症中起重要作用。虽然狭窄主动脉瓣的 AVIC 对 Toll 样受体 4（TLR4）刺激的反应增强，但潜在机制尚不清楚。本研究检验了这样一个假设，即 TLR4 和 Notch1 途径之间的过度串扰是导致狭窄瓣膜 AVIC 对脂多糖（LPS）的炎症反应增强的原因。
方法和结果
从正常和狭窄瓣叶中分离出人 AVIC。用 LPS 处理后分析核因子 kappa-B（NF-κB）的激活和白细胞介素-8、单核细胞趋化蛋白-1 和细胞间黏附分子-1 的产生。使用抑制剂、siRNA 和特异性配体确定 Notch1 在炎症反应中的作用。患病瓣膜的细胞产生了更高水平的趋化因子和细胞间黏附分子-1，与 NF-κB 激活增强相关。有趣的是，患病细胞在 TLR4 刺激后表现出 Jagged1 释放和 Notch1 激活的增强。 Notch1 的抑制和沉默都导致患病细胞中 TLR4 诱导的炎症反应得到更大程度的抑制。相反，用特异性配体 Jagged1 激活 Notch1 增强了正常 AVIC 中 LPS 诱导的炎症反应。此外，LPS 刺激后 Notch1 细胞内结构域与 NF-κB 激酶抑制剂共免疫沉淀， Notch1 的抑制消除了患病和正常细胞之间 NF-κB 激活水平的差异。
结论
Notch1 通过调节 NF-κB 激活增强人 AVIC 对 TLR4 刺激的炎症反应。 TLR4 和 Notch1 途径之间的过度串扰是导致狭窄瓣膜 AVIC 中 TLR4 反应增强的原因。
Zotero 插件