Ji Yuanyuan, Wang Zhidong, Li Zongfang, Liu Juntian
Scientific Research Center, School of Medicine, Xi'an Jiaotong University, Xi'an 710004, China.
Cell Physiol Biochem. 2010;25(6):631-40. doi: 10.1159/000315082. Epub 2010 May 18.
Lipopolysaccharide (LPS) induced-vascular inflammation plays a central role in vasculitis and atherosclerosis. The stimulation of toll-like receptor 4 (TLR4) by LPS elicits the release of major proinflammatory cytokines that aggravates cardiovascular disorders. Peroxisome proliferator- activated receptor alpha (PPARalpha) agonists have been shown to reduce cardiovascular events by controlling lipid metabolism as well as inflammation. However, the role of PPARalpha agonist fenofibrate in modulating LPS-mediated inflammatory responses in vascular smooth muscle cells (VSMCs) remains elusive. The present study demonstrated that fenofibrate exerted a potent anti-inflammatory action through reducing interleckin-1(IL-18), tissue inhibitor of metalloproteinase-1(TIMP-1), TLR4 and enhancing PPARalpha in LPS-stimulated VSMCs. Additionally, treatment of VSMCs with the TLR4 inhibition or TLR4 small-interfering RNA illustrated that the modulatory effects of fenofibrate on LPS-mediated inflammatory responses in VSMCs were reliant on TLR4. Especially, the results suggested that beneficial effects of fenofibrate on LPS-stimulated inflammatory responses in VSMCs were mediated through interference of TLR4 and its downstream signaling components such as Toll-interleckin-1(IL-1) receptor domain- containing adaptor inducing interferon-beta (TRIF), interferon regulatory factor 3 (IRF3) and interferon-gamma inducible protein 10 (IP-10). In conclusion, PPARalpha agonist fenofibrate exerts anti-inflammatory property by antagonizing LPS-mediated inflammatory responses in VSMCs. More importantly, the modulation of the TRIF-dependent signaling pathway (TLR4/TRIF/IRF3/IP-10) might be a useful and novel anti-inflammatory strategy of fenofibrate.
脂多糖（LPS）诱导的血管炎症在血管炎和动脉粥样硬化中起核心作用。LPS对Toll样受体4（TLR4）的刺激引发主要促炎细胞因子的释放，从而加重心血管疾病。过氧化物酶体增殖物激活受体α（PPARα）激动剂已被证明可通过控制脂质代谢和炎症来减少心血管事件。然而，PPARα激动剂非诺贝特在调节血管平滑肌细胞（VSMC）中LPS介导的炎症反应中的作用仍不清楚。本研究表明，非诺贝特通过降低脂多糖刺激的血管平滑肌细胞中的白细胞介素-1（IL-18）、金属蛋白酶组织抑制剂-1（TIMP-1）、TLR4并增强PPARα发挥强大的抗炎作用。此外，用TLR4抑制剂或TLR4小干扰RNA处理血管平滑肌细胞表明，非诺贝特对血管平滑肌细胞中LPS介导的炎症反应的调节作用依赖于TLR4。特别是，结果表明非诺贝特对脂多糖刺激的血管平滑肌细胞炎症反应的有益作用是通过干扰TLR4及其下游信号成分，如含Toll-白细胞介素-1（IL-1）受体结构域的衔接蛋白诱导干扰素-β（TRIF）、干扰素调节因子3（IRF3）和干扰素-γ诱导蛋白10（IP-10）介导的。总之，PPARα激动剂非诺贝特通过拮抗血管平滑肌细胞中LPS介导的炎症反应发挥抗炎特性。更重要的是，调节TRIF依赖的信号通路（TLR4/TRIF/IRF3/IP-10）可能是非诺贝特一种有用的新型抗炎策略。
