Atorvastatin and Simvastatin, but not Pravastatin, Up-regulate LPS-Induced MMP-9 Expression in Macrophages by Regulating Phosphorylation of ERK and CREB

Cellular Physiology and Biochemistry

关键词: CREB;    ERK;    Macrophage;    LPS;    MMP-9;    Statin;   

DOI  :  10.1159/000341433

学科分类：分子生物学，细胞生物学和基因

来源: S Karger AG

【 摘 要 】

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.

【 授权许可】

CC BY-NC-ND