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

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-&kgr;B (NF-&kgr;B), a transcription factor, is necessary for metalloproteinase secretion and, hence, is a target for pharmacological intervention. Adenovirus-mediated gene transfer of the inhibitory NF-&kgr;B subunit, I-&kgr; B&agr;, was achieved into human monocyte-derived macrophages in vitro and into foam cells produced in vivo in cholesterol-fed rabbits. Human macrophages and rabbit foam cells secreted matrix-degrading metalloproteinase (MMP)-9 without further stimulation, and this was not inhibited by I-&kgr;B&agr; (11±16% and 8±10%, respectively;P > 0.05). MMP-1 secretion from human macrophages increased in response to recombinant human CD40 ligand and was inhibited 92±5% by I-&kgr;B&agr; (n=3, P <0.05). Rabbit foam cells secreted MMP-1 and -3 without further stimulation, and this was inhibited 83±12% and 69±11%, respectively, by I-&kgr;B&agr; (n=6 or 7, P <0.001). I-&kgr;B&agr; did not significantly affect the expression or activity of tissue inhibitor of metalloproteinases-1 or -2. Overexpression of I-&kgr;B&agr; inhibited collagenolytic and &bgr;-caseinolytic activity by 42±2% and 41±7%, respectively (n=3, P <0.05). Secretion of MMP-1 and MMP-3 from macrophages stimulated in vitro or in vivo depends on the activation of NF-&kgr;B. Because the inhibition of NF-&kgr;B reduces proteolytic activity, it appears to be an attractive pharmacological target in unstable atheromas.