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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.

Original publication




Journal article


Proceedings of the National Academy of Sciences of the United States of America

Publication Date





5634 - 5639


Kennedy Institute of Rheumatology, Imperial College, Charing Cross Campus, London W6 8LH, United Kingdom.


Cells, Cultured, Myocytes, Smooth Muscle, Humans, Adenoviridae, Arteriosclerosis, Thrombosis, Inflammation, Actins, Matrix Metalloproteinases, Protein-Serine-Threonine Kinases, Thromboplastin, NF-kappa B, CD40 Ligand, Tissue Inhibitor of Metalloproteinase-1, Interleukin-8, Antigens, CD3, Interleukin-6, Gene Transfer, Horizontal, I-kappa B Kinase, Transcription Factor RelA, NF-kappa B p50 Subunit, Matrix Metalloproteinase Inhibitors