Atorvastatin and Simvastatin, but not Pravastatin, Up-regulate LPS-Induced MMP-9 Expression in Macrophages by Regulating Phosphorylation of ERK and CREB
- Authors
- Lee, Dong Kun; Park, Eun Ju; Kim, Eun Kyoung; Jin, JunYup; Kim, Jong Soo; Shin, Ik Jae; Kim, Bo-Yeon; Lee, Hookeun; Kim, Dong-Eog
- Issue Date
- 2012
- Publisher
- KARGER
- Keywords
- ' CREB; ERK; Macrophage; LPS; MMP-9; Statin
- Citation
- CELLULAR PHYSIOLOGY AND BIOCHEMISTRY, v.30, no.3, pp.499 - 511
- Journal Title
- CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
- Volume
- 30
- Number
- 3
- Start Page
- 499
- End Page
- 511
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/17564
- DOI
- 10.1159/000341433
- ISSN
- 1015-8987
- Abstract
- 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
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