Title

Toll-like receptor 3 signaling evokes a proinflammatory and proliferative phenotype in human vascular smooth muscle cells

UMMS Affiliation

Department of Medicine, Division of Infectious Diseases and Immunology

Publication Date

2006-06-20

Document Type

Article

Subjects

Adolescent; Adult; Cell Culture Techniques; Cell Division; Cells, Cultured; Child, Preschool; Coronary Vessels; Female; Humans; Male; Muscle, Smooth, Vascular; Phenotype; Pulmonary Artery; Signal Transduction; Toll-Like Receptor 3; Vasculitis

Disciplines

Immunology and Infectious Disease

Abstract

Inflammation plays a key role in atherogenesis, perhaps promoted by bacterial and viral products present within the artery wall. Vascular smooth muscle cells (VSMC) can express certain bacterially responsive Toll-like receptors (TLR), which promote a proinflammatory and proliferative VSMC phenotype when activated, but it is unknown whether virally activated TLR can regulate VSMC phenotype. Here we tested the role in VSMC of TLR3, which is activated by double-stranded (dsRNA), a molecular signature of viruses. VSMC from multiple vessel types, including human coronary artery (HCoASMC) and mouse aorta (MAoSMC), expressed TLR3 constitutively, and HCoASMC were exquisitely sensitive to dsRNA-stimulated release of monocyte chemoattractant protein-1 (MCP-1) and interleukin-6. dsRNA-induced MCP-1 release was abolished by small interfering RNA-mediated TLR3 knockdown in HCoASMC and was absent in TLR3-/- MAoSMC but was unimpaired in TLR2-/- and in TLR4 signaling-deficient MAoSMC. Exposure to dsRNA also activated ERK1/2 and NF-kappaB in both human and murine SMC, but these effects were absent in SMC from TLR3-deficient mice, demonstrating a crucial role of TLR3 signaling. dsRNA also stimulated proliferation of HCoASMC, indicated by increased DNA synthesis, and induced persistent elevations in the intracellular levels of growth-promoting mediators, including interleukin-1alpha and phospho-ERK1/2. We conclude that exposure of HCoASMC to dsRNA elicits dramatic TLR3-mediated proinflammatory and proproliferative phenotypic changes, responses that could potentially be triggered by viral infection of cells within the arterial wall.

DOI of Published Version

10.1152/ajpheart.00252.2006

Source

Am J Physiol Heart Circ Physiol. 2006 Nov;291(5):H2334-43. Epub 2006 Jun 16. Link to article on publisher's site

Journal/Book/Conference Title

American journal of physiology. Heart and circulatory physiology

Related Resources

Link to Article in PubMed

PubMed ID

16782847

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