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
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / immunology
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Adenoviridae / genetics
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Arteriosclerosis / immunology
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Arteriosclerosis / metabolism*
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Arteriosclerosis / pathology
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CD3 Complex / immunology
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CD40 Ligand / immunology
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CD40 Ligand / metabolism
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Cells, Cultured
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Gene Transfer, Horizontal
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Humans
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I-kappa B Kinase
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Inflammation / immunology
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Inflammation / metabolism
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Inflammation / pathology
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Interleukin-6 / biosynthesis
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Interleukin-8 / biosynthesis
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Matrix Metalloproteinase Inhibitors
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Matrix Metalloproteinases / biosynthesis
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Myocytes, Smooth Muscle / cytology
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism*
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NF-kappa B p50 Subunit
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NF-kappaB-Inducing Kinase
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Thromboplastin / biosynthesis
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Thrombosis / immunology
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Thrombosis / metabolism*
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Thrombosis / pathology
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Tissue Inhibitor of Metalloproteinase-1 / biosynthesis
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Transcription Factor RelA
Substances
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Actins
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CD3 Complex
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Interleukin-6
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Interleukin-8
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Matrix Metalloproteinase Inhibitors
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NF-kappa B
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NF-kappa B p50 Subunit
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Tissue Inhibitor of Metalloproteinase-1
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Transcription Factor RelA
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CD40 Ligand
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Thromboplastin
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Protein Serine-Threonine Kinases
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CHUK protein, human
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I-kappa B Kinase
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IKBKB protein, human
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IKBKE protein, human
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Matrix Metalloproteinases