Atorvastatin and Simvastatin, but not Pravastatin, Up-regulate LPS-Induced MMP-9 Expression in Macrophages by Regulating Phosphorylation of ERK and CREB
Atorvastatin and Simvastatin, but not Pravastatin, Up-regulate LPS-Induced MMP-9 Expression in Macrophages by Regulating Phosphorylation of ERK and CREB
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DOI：
10.1159/000341433
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发表时间：
2012-01-01
影响因子：
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通讯作者：
Kim, Dong-Eog
中科院分区：
文献类型：
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作者：
Lee, Dong Kun;Park, Eun Ju;Kim, Dong-Eog
他汀类药物抑制内皮细胞中促炎细胞因子的表达，而它们增强免疫细胞中促炎细胞因子的表达。促炎细胞因子和脂多糖（LPS）诱导巨噬细胞中基质金属蛋白酶（MMP）-9基因表达，其与各种炎性疾病的进展有关。本研究的目的是确定各种他汀类药物对LPS诱导的巨噬细胞和小胶质细胞MMP-9基因表达的影响。MMP-9表达通过实时PCR或酶谱分析。通过时间依赖性的信号分子磷酸化来分析他汀类药物对信号通路激活的影响。阿托伐他汀和辛伐他汀，但不是普伐他汀，上调LPS诱导的MMP-9在小鼠RAW 264.7巨噬细胞和BV 2小胶质细胞的表达。辛伐他汀可延长细胞外信号调节激酶的磷酸化持续时间，而阿托伐他汀或普伐他汀则无此作用。他汀类药物上调LPS诱导的MMP-9基因表达依赖于细胞外钙离子，并通过增强cAMP反应元件结合蛋白的磷酸化介导。胆固醇合成前体香叶基香叶基焦磷酸可抑制阿托伐他汀和辛伐他汀对LPS介导的MMP-9基因表达的上调。阿托伐他汀和辛伐他汀介导的体外巨噬细胞和小胶质细胞中LPS诱导的MMP-9基因表达上调引起了人们对在某些由LPS介导的炎症性疾病中使用广泛处方的他汀类药物的重要关注。版权所有（C）2012 S. Karger AG，巴塞尔
Statins suppress expression of pro-inflammatory cytokines in endothelial cells, whereas they enhance it in immune cells. Pro-inflammatory cytokines and lipopolysaccharide (LPS) induce matrix metalloproteinase (MMP)-9 gene expression in macrophages, which has been linked to progress of various inflammatory diseases. The aim of this study was to identify effects of various statins on LPS-induced MMP-9 gene expression in macrophages and microglia. MMP-9 expression was analyzed by real-time PCR or zymography. Effect of statins on activation of signaling pathways was analyzed by time-dependent phosphorylation of signaling molecules. Atorvastatin and simvastatin, but not pravastatin, up-regulated LPS-induced MMP-9 expression in murine RAW 264.7 macrophages and BV2 microglia. The phosphorylation duration of extracellular signal regulated kinases was extended by simvastatin, but not by atorvastatin or pravastatin. The up-regulation of LPS-induced MMP-9 gene expression by the statins was dependent on extracellular calcium ions and mediated by enhancing phosphorylation of cAMP-responsive element binding protein. Geranylgeranyl pyrophosphate, a precursor for cholesterol synthesis, could suppress up-regulation of LPS-mediated MMP-9 gene expression by atorvastatin and simvastatin. Atorvastatin and simvastatin-mediated up-regulation of LPS-induced MMP-9 gene expression in macrophages and microglia in vitro raises an important concern about use of the widely-prescribed statins in certain inflammatory conditions that are mediated by LPS. Copyright (C) 2012 S. Karger AG, Basel