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Published online before print July 14, 2008

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(Journal of Leukocyte Biology. 2008;84:1120-1129.)
© 2008 by Society for Leukocyte Biology

Simvastatin suppresses LPS-induced MMP-1 expression in U937 mononuclear cells by inhibiting protein isoprenylation-mediated ERK activation

Kamala P. Sundararaj^*, Devadoss J. Samuvel^*, Yanchun Li, Alena Nareika^*, Elizabeth H. Slate, John J. Sanders, Maria F. Lopes-Virella^*, and Yan Huang^*,,1

Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina, USA; and
^* Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine,
Department of Biostatistics, Bioinformatics and Epidemiology, and
Division of Periodontics, Department of Stomatology, Medical University of South Carolina, Charleston, South Carolina, USA

¹ Correspondence: Ralph H. Johnson Veterans Affairs Medical Center and Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina, 114 Doughty St., Charleston, SC 29403, USA. E-mail: huangyan{at}musc.edu

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-B 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.

Key Words: matrix metalloproteinases • statin • lipopolysaccharide • mitogen-activated protein kinase • gene expression