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Simvastatin suppresses LPS-induced MMP-1 expression in U937 mononuclear cells by inhibiting protein isoprenylation-mediated ERK activation
- Source :
- Journal of Leukocyte Biology. 84:1120-1129
- Publication Year :
- 2008
- Publisher :
- Oxford University Press (OUP), 2008.
-
Abstract
- Matrix metalloproteinase (MMP) plays a crucial role in periodontal disease and is up-regulated by oral Gram-negative, pathogen-derived LPS. In this study, we reported that simvastatin, a 3-hydroxyl-3-methylglutaryl-CoA reductase inhibitor, effectively inhibited LPS-stimulated MMP-1 as well as MMP-8 and MMP-9 expression by U937 mononuclear cells. Our studies showed that the geranylgeranyl transferase inhibitor inhibited LPS-stimulated MMP-1 expression, and addition of isoprenoid intermediate geranylgeranyl pyrophosphate (GGPP) reduced the inhibitory effect of simvastatin on LPS-stimulated MMP-1 expression. We also demonstrated that simvastatin inhibited the activation of Ras and Rac, and the inhibition was abolished by addition of GGPP. The above results indicate that protein isoprenylation is involved in the regulation of MMP-1 expression by LPS and simvastatin. Moreover, we showed that simvastatin inhibited LPS-stimulated nuclear AP-1, but not NF-κB activity, and the inhibition was reversed by addition of GGPP. Simvastatin also inhibited LPS-stimulated ERK but not p38 MAPK and JNK. Finally, we showed that the inhibition of LPS-stimulated ERK activation by simvastatin was reversed by GGPP. Taken together, this study showed that simvastatin suppresses LPS-induced MMP-1 expression in U937 mononuclear cells by targeting protein isoprenylation-mediated ERK activation.
- Subjects :
- Lipopolysaccharides
MAPK/ERK pathway
Simvastatin
Geranylgeranyl Transferase
Statin
Geranylgeranyl pyrophosphate
medicine.drug_class
p38 mitogen-activated protein kinases
Immunology
Biology
Polymerase Chain Reaction
Gene Expression Regulation, Enzymologic
chemistry.chemical_compound
polycyclic compounds
medicine
Humans
Immunology and Allergy
Extracellular Signal-Regulated MAP Kinases
U937 cell
nutritional and metabolic diseases
U937 Cells
Cell Biology
Molecular biology
Neoplasm Proteins
Enzyme Activation
chemistry
Mitogen-activated protein kinase
biology.protein
lipids (amino acids, peptides, and proteins)
Receptors, Signal Transduction, and Genes
Matrix Metalloproteinase 1
Transcription Factors
medicine.drug
Subjects
Details
- ISSN :
- 19383673 and 07415400
- Volume :
- 84
- Database :
- OpenAIRE
- Journal :
- Journal of Leukocyte Biology
- Accession number :
- edsair.doi.dedup.....3003d810ce1b1337495c05168cc39c25