Wang Xiao Qiao, Luo Nian Sang, Salah Zhong Qing Chen, Lin Yong Qing, Gu Miao Ning, Chen Yang Xin
Department of Anesthesiology, Nanfang Hospital of Southern Medical University, Guangzhou 510515, Guangdong, China; Department of Anesthesiology, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, Guangdong, China.
Department of Cardiology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou 510120, Guangdong, China; Guangdong Provincial Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou 510120, Guangdong, China.
Biomed Environ Sci. 2014 Oct;27(10):786-93. doi: 10.3967/bes2014.114.
To assess the effect of atorvastatin on lipopolysaccharide (LPS)-induced TNF-α production in RAW264.7 macrophages.
RAW264.7 macrophages were treated in different LPS concentrations or at different time points with or without atorvastatin. TNF-α level in supernatant was measured. Expressions of TNF-α mRNA and protein and heme oxygenase-1 (HO-1) were detected by ELISA, PCR, and Western blot, respectively. HO activity was assayed.
LPS significantly increased the TNF-α expression and secretion in a dose- and time-dependent manner. The HO-1 activity and HO-1 expression level were significantly higher after atorvastatin treatment than before atorvastatin treatment and attenuated by SB203580 and PD98059 but not by SP600125, suggesting that the ERK and p38 mitogen-activated protein kinase (MAPK) pathways participate in regulating the above-mentioned effects of atorvastatin. Moreover, the HO-1 activity suppressed by SnPP or the HO-1 expression inhibited by siRNA significantly attenuated the effect of atorvastatin on TNF-α expression and production in LPS-stimulated macrophages.
Atorvastatin can attenuate LPS-induced TNF-α expression and production by activating HO-1 via the ERK and p38 MAPK pathways, suggesting that atorvastatin can be used in treatment of inflammatory diseases such as sepsis, especially in those with atherosclerotic diseases.
评估阿托伐他汀对脂多糖（LPS）诱导的RAW264.7巨噬细胞中肿瘤坏死因子-α（TNF-α）产生的影响。
用不同浓度的LPS或在不同时间点对RAW264.7巨噬细胞进行处理，同时加入或不加入阿托伐他汀。检测上清液中TNF-α水平。分别通过酶联免疫吸附测定（ELISA）、聚合酶链反应（PCR）和蛋白质印迹法检测TNF-α mRNA和蛋白以及血红素加氧酶-1（HO-1）的表达。测定HO活性。
LPS以剂量和时间依赖性方式显著增加TNF-α的表达和分泌。阿托伐他汀处理后HO-1活性和HO-1表达水平显著高于处理前，且被SB203580和PD98059减弱，但未被SP600125减弱，这表明细胞外信号调节激酶（ERK）和p38丝裂原活化蛋白激酶（MAPK）通路参与调节阿托伐他汀的上述作用。此外，锡原卟啉（SnPP）抑制HO-1活性或小干扰RNA（siRNA）抑制HO-1表达均显著减弱阿托伐他汀对LPS刺激的巨噬细胞中TNF-α表达和产生的影响。
阿托伐他汀可通过ERK和p38 MAPK通路激活HO-1，从而减弱LPS诱导的TNF-α表达和产生，这表明阿托伐他汀可用于治疗脓毒症等炎症性疾病，尤其是合并动脉粥样硬化疾病的患者。
