Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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

DOI

10.1073/pnas.0401060101

Type

Journal article

Journal

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

Publication Date

02/04/2004

Volume

101

Pages

5634 - 5639

Addresses

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

Keywords

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