Canonical pathway of nuclear factor kappa B activation selectively regulates proinflammatory and prothrombotic responses in human atherosclerosis.
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.
Monaco
Claudia
C
Kennedy Institute of Rheumatology, Imperial College, Charing Cross Campus, London W6 8LH, United Kingdom.
Andreakos
Evangelos
E
Kiriakidis
Serafim
S
Mauri
Claudia
C
Bicknell
Colin
C
Foxwell
Brian
B
Cheshire
Nicholas
N
Paleolog
Ewa
E
Feldmann
Marc
M
D000199:Actins / Q000276:immunology; D000256:Adenoviridae / Q000235:genetics; D001161:Arteriosclerosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D017252:CD3 Complex / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D022761:Gene Transfer, Horizontal; D006801:Humans; D051550:I-kappa B Kinase; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D013925:Thromboplastin / Q000096:biosynthesis; D013927:Thrombosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis; D051996:Transcription Factor RelA; D000097782:NF-kappaB-Inducing Kinase
D000199:Actins; D017252:CD3 Complex; D023201:CD40 Ligand; D051550:I-kappa B Kinase; D015850:Interleukin-6; D016209:Interleukin-8; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D017346:Protein Serine-Threonine Kinases; D013925:Thromboplastin; D019715:Tissue Inhibitor of Metalloproteinase-1; D051996:Transcription Factor RelA; D000097782:NF-kappaB-Inducing Kinase; C496559:CHUK protein, human; C496560:IKBKB protein, human; C496565:IKBKE protein, human