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1 Molecular Cardiology Research Institute, Tufts-New England Medical Center, Boston, Ma, USA
2 Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Ma, USA
* To whom correspondence should be addressed. E-mail: dbeasley{at}tufts-nemc.org.
Recent evidence supports a role of Toll-like receptor (TLR) signaling in the development of atherosclerotic lesions. In this study, we tested whether TLR4 signaling promotes a proinflammatory phenotype in human and mouse arterial smooth muscle cells (SMC), characterized by the synthesis of cytokines and chemokines, and increased TLR expression. Human arterial SMC were found to express mRNA encoding TLR4, and the TLR4-associated molecules, MD-2 and CD14, but not TLR2 mRNA. Mouse aortic SMC, on the other hand, expressed both TLR2 and TLR4 mRNA constitutively. Human SMC derived from coronary artery, but not those from pulmonary artery, were found to express cell surface-associated CD14. Low (ng/ml) concentrations of E. coli lipopolysaccharide (LPS), the prototypical TLR4 agonist, markedly stimulated ERK1/2 activity, induced release of monocyte-chemoattractant protein-1 (MCP-1) and IL-6, and stimulated IL-1
expression in human aortic SMC, and exogenous CD14 enhanced these effects. Expression of a dominant negative form of TLR4 in human SMC attenuated LPS-induced ERK1/2 and MCP-1 release. LPS was a potent inducer of NF-kB activity, ERK1/2 phosphorylation, MCP-1 release, and TLR2 mRNA expression in wild-type, but not TLR4-signaling deficient mouse aortic SMC. These studies show that TLR4 signaling promotes a proinflammatory phenotype in VSMC, and suggest that VSMC may potentially play an active role in vascular inflammation via the release of chemokines, pro-inflammatory cytokines, and increased expression of TLR2.
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