Inhibition of Tumor Necrosis Factor-α-Induced Interleukin-6 Expression by Telmisartan Through Cross-Talk of Peroxisome Proliferator-Activated Receptor-γ With Nuclear Factor κB and CCAAT/Enhancer- Binding Protein-β
Inhibition of Tumor Necrosis Factor-α-Induced Interleukin-6 Expression by Telmisartan Through Cross-Talk of Peroxisome Proliferator-Activated Receptor-γ With Nuclear Factor κB and CCAAT/Enhancer- Binding Protein-β
复制标题
DOI：
10.1161/hypertensionaha.108.126656
复制
发表时间：
2009-05-01
期刊：
影响因子：
8.3
通讯作者：
Sunagawa, Kenji
中科院分区：
文献类型：
--
作者：
Tian, Qingping;Miyazaki, Ryohei;Sunagawa, Kenji
据报告，替米沙坦是一种血管紧张素II 1型受体拮抗剂，是过氧化物酶体增殖物激活受体-γ的部分激动剂。尽管已证明过氧化物酶体增殖物激活受体-γ激活剂具有抗炎作用，如抑制细胞因子产生，但尚未确定替米沙坦是否具有此类作用。我们研究了替米沙坦是否抑制血管平滑肌细胞中促炎细胞因子白细胞介素-6（IL-6）的表达。替米沙坦（而非缬沙坦）可减弱肿瘤坏死因子-α（TNF-α）诱导的IL-6 mRNA表达。替米沙坦以剂量依赖性方式降低TNF-α诱导的IL-6 mRNA和蛋白表达。由于IL-6 mRNA表达的抑制被GW9662预处理所阻止，GW9662是一种特异性过氧化物酶体增殖物激活受体-γ拮抗剂，过氧化物酶体增殖物激活受体-γ可能参与该过程。替米沙坦抑制TNF-α诱导的IL-6基因启动子活性。缺失分析表明，IL-6基因启动子-150 bp至-27 bp之间的DNA片段（包含核因子κ B和CCAAT/增强子结合蛋白-β位点）负责替米沙坦抑制。替米沙坦减弱TNF-α诱导的核因子κ B和CCAAT/增强子结合蛋白-β依赖性基因转录和DNA结合。替米沙坦还降低了TNF-α输注小鼠的血清IL-6水平和TNF-α体外刺激大鼠主动脉的IL-6产生。这些数据表明，除了阻断血管紧张素II 1型受体外，替米沙坦还可减弱TNF-α诱导的炎症过程。由于TNF-α和血管紧张素II通过增强血管炎症在动脉粥样硬化形成中发挥重要作用，因此替米沙坦不仅可用于治疗高血压，还可用于治疗血管炎症变化。（高血压。2009; 53：798 - 804.）
Telmisartan, an angiotensin II type 1 receptor antagonist, was reported to be a partial agonist of peroxisome proliferator-activated receptor-gamma. Although peroxisome proliferator-activated receptor-gamma activators have been shown to have an anti-inflammatory effect, such as inhibition of cytokine production, it has not been determined whether telmisartan has such effects. We examined whether telmisartan inhibits expression of interleukin-6 (IL-6), a proinflammatory cytokine, in vascular smooth muscle cells. Telmisartan, but not valsartan, attenuated IL-6 mRNA expression induced by tumor necrosis factor-alpha (TNF-alpha). Telmisartan decreased TNF-alpha-induced IL-6 mRNA and protein expression in a dose-dependent manner. Because suppression of IL-6 mRNA expression was prevented by pretreatment with GW9662, a specific peroxisome proliferator-activated receptor-gamma antagonist, peroxisome proliferator-activated receptor-gamma may be involved in the process. Telmisartan suppressed IL-6 gene promoter activity induced by TNF-alpha. Deletion analysis suggested that the DNA segment between -150 bp and -27 bp of the IL-6 gene promoter that contains nuclear factor kappa B and CCAAT/enhancer-binding protein-beta sites was responsible for telmisartan suppression. Telmisartan attenuated TNF-alpha-induced nuclear factor kappa B- and CCAAT/enhancer-binding protein-beta-dependent gene transcription and DNA binding. Telmisartan also attenuated serum IL-6 level in TNF-alpha-infused mice and IL-6 production from rat aorta stimulated with TNF-alpha ex vivo. These data suggest that telmisartan may attenuate inflammatory process induced by TNF-alpha in addition to the blockade of angiotensin II type 1 receptor. Because both TNF-alpha and angiotensin II play important roles in atherogenesis through enhancement of vascular inflammation, telmisartan may be beneficial for treatment of not only hypertension but also vascular inflammatory change. (Hypertension. 2009; 53: 798-804.)