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

Nuclear factor kappaB (NF-kappaB) 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-kappaB is activated in these cells and that this activity involves p65, p50, and c-Rel but not p52 or RelB. This NF-kappaB activation can be blocked by overexpression of IkappaBalpha or dominant-negative IkappaB kinase (IKK)-2 but not dominant-negative IKK-1 or NF-kappaB-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 anti inflammatory cytokine IL-10 or tissue inhibitor of matrix metalloproteinases. Our results demonstrate that the canonical pathway of NF-kappaB activation that involves p65, p50, c-Rel, and IKK-2 is activated in human atherosclerosis and results in selective upregulation of major proinflammatory and prothrombotic mediators of the disease.