Atorvastatin and simvastatin, but not pravastatin, up-regulate LPS-induced MMP-9 expression in macrophages by regulating phosphorylation of ERK and CREB.
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.
Laboratory of Genome to Drug Medicine, Joint Center for Biosciences, Incheon, Korea. dklee.jcb@gmail.com
Dong Kun
DK
Lee
Eun Ju
EJ
Park
Eun Kyoung
EK
Kim
JunYup
J
Jin
Jong Soo
JS
Kim
Ik Jae
IJ
Shin
Bo-Yeon
BY
Kim
Hookeun
H
Lee
Dong-Eog
DE
Kim
D000818:Animals; D000069059:Atorvastatin; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006538:Heptanoic Acids / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000378:metabolism; D010766:Phosphorylation; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D017035:Pravastatin / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D015398:Signal Transduction; D019821:Simvastatin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects*
D017362:Cyclic AMP Response Element-Binding Protein; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008070:Lipopolysaccharides; D011106:Polyisoprenyl Phosphates; D011758:Pyrroles; D000069059:Atorvastatin; D019821:Simvastatin; D048049:Extracellular Signal-Regulated MAP Kinases; D020780:Matrix Metalloproteinase 9; D017035:Pravastatin; C002963:geranylgeranyl pyrophosphate; D002118:Calcium