Toll-like receptor 4 mediates inflammatory cytokine secretion in smooth muscle cells induced by oxidized low-density lipoprotein

PLoS One. 2014 Apr 22;9(4):e95935. doi: 10.1371/journal.pone.0095935. eCollection 2014.

Abstract

Oxidized low-density lipoprotein (oxLDL)-regulated secretion of inflammatory cytokines in smooth muscle cells (SMCs) is regarded as an important step in the progression of atherosclerosis; however, its underlying mechanism remains unclear. This study investigated the role of toll-like receptor 4 (TLR4) in oxLDL-induced expression of inflammatory cytokines in SMCs both in vivo and in vitro. We found that the levels of TLR4, interleukin 1-β (IL1-β), tumor necrosis factor-α (TNFα), monocyte chemoattractant protein 1 (MCP-1) and matrix metalloproteinase-2 (MMP-2) expression were increased in the SMCs of atherosclerotic plaques in patients with femoral artery stenosis. In cultured primary arterial SMCs from wild type mice, oxLDL caused dose- and time-dependent increase in the expression levels of TLR4 and cytokines. These effects were significantly weakened in arterial SMCs derived from TLR4 knockout mice (TLR4-/-). Moreover, the secretion of inflammatory cytokines was blocked by TLR4-specific antibodies in primary SMCs. Ox-LDL induced activation of p38 and NFκB was also inhibited in TLR4-/- primary SMCs or when treated with TLR4-specific antibodies. These results demonstrated that TLR4 is a crucial mediator in oxLDL-induced inflammatory cytokine expression and secretion, and p38 and NFκB activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Cells, Cultured
  • Cytokines / metabolism*
  • Humans
  • Inflammation Mediators / physiology
  • Lipoproteins, LDL / physiology*
  • Male
  • Matrix Metalloproteinase 2 / metabolism
  • Mice, Inbred C57BL
  • Muscle, Smooth, Vascular / immunology
  • Muscle, Smooth, Vascular / metabolism
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Smooth Muscle / metabolism*
  • Plaque, Atherosclerotic / immunology
  • Plaque, Atherosclerotic / metabolism
  • Plaque, Atherosclerotic / pathology
  • Primary Cell Culture
  • Toll-Like Receptor 4 / physiology*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Cytokines
  • Inflammation Mediators
  • Lipoproteins, LDL
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • oxidized low density lipoprotein
  • p38 Mitogen-Activated Protein Kinases
  • MMP2 protein, human
  • Matrix Metalloproteinase 2

Grant support

This work was supported by grants from the National Natural Science Foundation of China (30900521/H0206 and 81200204/H0215) and a grant from municipal government (10JC1410501). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.