Canonical pathway of nuclear factor kappa B activation selectively regulates proinflammatory and prothrombotic responses in human atherosclerosis

Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5634-9. doi: 10.1073/pnas.0401060101. Epub 2004 Apr 2.

Abstract

Nuclear factor kappa B (NF-kappa B) activation has been observed in human atherosclerotic plaques and is enhanced in unstable coronary plaques, but whether such activation has a protective or pathophysiological role remains to be determined. We addressed this question by developing a short-term culture system of cells isolated from human atherosclerotic tissue, allowing efficient gene transfer to directly investigate signaling pathways in human atherosclerosis. We found that NF-kappa B is activated in these cells and that this activity involves p65, p50, and c-Rel but not p52 or RelB. This NF-kappa B activation can be blocked by overexpression of I kappa B alpha or dominant-negative I kappa B kinase (IKK)-2 but not dominant-negative IKK-1 or NF-kappa B-inducing kinase, resulting in selective inhibition of inflammatory cytokines (tumor necrosis factor alpha, IL-6, and IL-8), tissue factor, and matrix metalloproteinases without affecting the antiinflammatory cytokine IL-10 or tissue inhibitor of matrix metalloproteinases. Our results demonstrate that the canonical pathway of NF-kappa B activation that involves p65, p50, c-Rel, and IKK-2 is activated in human atherosclerosis and results in selective up-regulation of major proinflammatory and prothrombotic mediators of the disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / immunology
  • Adenoviridae / genetics
  • Arteriosclerosis / immunology
  • Arteriosclerosis / metabolism*
  • Arteriosclerosis / pathology
  • CD3 Complex / immunology
  • CD40 Ligand / immunology
  • CD40 Ligand / metabolism
  • Cells, Cultured
  • Gene Transfer, Horizontal
  • Humans
  • I-kappa B Kinase
  • Inflammation / immunology
  • Inflammation / metabolism
  • Inflammation / pathology
  • Interleukin-6 / biosynthesis
  • Interleukin-8 / biosynthesis
  • Matrix Metalloproteinase Inhibitors
  • Matrix Metalloproteinases / biosynthesis
  • Myocytes, Smooth Muscle / cytology
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • NF-kappa B p50 Subunit
  • NF-kappaB-Inducing Kinase
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Thromboplastin / biosynthesis
  • Thrombosis / immunology
  • Thrombosis / metabolism*
  • Thrombosis / pathology
  • Tissue Inhibitor of Metalloproteinase-1 / biosynthesis
  • Transcription Factor RelA

Substances

  • Actins
  • CD3 Complex
  • Interleukin-6
  • Interleukin-8
  • Matrix Metalloproteinase Inhibitors
  • NF-kappa B
  • NF-kappa B p50 Subunit
  • Tissue Inhibitor of Metalloproteinase-1
  • Transcription Factor RelA
  • CD40 Ligand
  • Thromboplastin
  • Protein Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Matrix Metalloproteinases