Role of Nuclear Factor-κB Activation in Metalloproteinase-1, -3, and -9 Secretion by Human Macrophages In Vitro and Rabbit Foam Cells Produced In Vivo

Abstract

Abstract-Metalloproteinase secretion by macrophages is believed to play a key role in the matrix degradation that underlies atherosclerotic plaque instability and aneurysm formation. We studied the hypothesis that nuclear factor-B (NF-B), a transcription factor, is necessary for metalloproteinase secretion and, hence, is a target for pharmacological intervention. Key Words: macrophages Ⅲ foam cells Ⅲ metalloproteinases Ⅲ nuclear factor-B R upture of the fibrous cap of the atherosclerotic plaque is a key event in triggering coronary thrombosis and acute coronary syndromes. Two characteristic pathological features of the rupture-prone plaque are increased macrophage density and reduced collagen content, associated with reduced tensile strength. 1,2 Overexpression of several matrix-degrading metalloproteinases (MMPs), including MMP-1, MMP-3, and MMP-9, has been demonstrated in human atherosclerotic plaques and in animal models 3,4 and is particularly associated with macrophages. Therefore, excessive production of macrophage-derived MMPs probably links increased macrophage density and loss of collagen. Consequently, inhibition of MMP production from macrophages could prove a valuable strategy for promoting plaque stability. Our recent work 5,6 has shown that inhibiting nuclear factor-B (NF-B), a transcription factor, prevents upregulation of MMP-1, MMP-3, and MMP-9 secretion from fibroblasts and vascular smooth muscle cells (SMCs). However, it is unknown whether this strategy would also reduce MMP secretion from macrophages. To investigate this possibility, we subjected human monocyte-derived macrophages to adenovirus-mediated overexpression of the inhibitory subunit, I-B␣, which has been shown previously to inhibit the secretion of tumor necrosis factor (TNF)-␣, interleukin (IL)-1␤, IL-6, and IL-8 from macrophages. 7 Although several available agents, including aspirin, statins, fibrates, and thiazolidinediones, probably exert part of their effects though reducing NF-B activity, there are presently no highly selective inhibitors that can be used in vivo. As a surrogate to evaluate the likely impact of NF-B inhibition in vivo, we extended our study of I-B␣ overexpression to the established model 8 of foam cells elicited in cholesterol-fed rabbits.

Interferon‐γ regulation of TNFα‐induced matrix metalloproteinase 3 expression and migration of human glioma T98G cells

“…17 In this report, we have made similar observations on MMP-3 induction in the T98G cells upon TNFa treatment. Additionally, our results showed that IFNg blocks the binding of Ets-1 and NFjB to their respective enhancer sequences, which are present in the MMP-3 promoter.…”

Suppression of cerebral aneurysm formation in rats by a tumor necrosis factor–α inhibitor

“…tion and formation of cerebral aneurysms in rat aneurysmal models. 4 Nuclear factor-kB also regulates the transcription of some proinflammatory genes such as iNOS 36 and matrix metalloproteinases (MMPs), 9 which are of functional importance for the progression of cerebral aneurysms. Recent reports have shown that regression of some inflammatoryrelated molecules have protective effects in experimental cerebral aneurysm models.…”

Smoking, Metalloproteinases, and Vascular Disease

“…The expression of the AP-1 transcription factor complex is positively associated with matrix metalloproteinase expression, 94,95 and cigarette smoke is associated with increased expression of AP-1. 96,97 Secretion of MMP-1 and MMP-3 from macrophages stimulated in vitro or in vivo depends on the activation of NF-B, 98 and NF-B is required for cytokine upregulation of MMP-1, MMP-3, and MMP-9 in VSMCs. 99 Cigarette smoke itself is associated with activation of NF-B.…”