Role of nuclear factor-kappa B activation in metalloproteinase-1, -3, and -9 secretion by human macrophages in vitro and rabbit foam cells produced in vivo.
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-kappaB (NF-kappaB), a transcription factor, is necessary for metalloproteinase secretion and, hence, is a target for pharmacological intervention. Adenovirus-mediated gene transfer of the inhibitory NF-kappaB subunit, I-kappa Balpha, 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-kappaBalpha (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-kappaBalpha (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-kappaBalpha (n=6 or 7, P<0.001). I-kappaBalpha did not significantly affect the expression or activity of tissue inhibitor of metalloproteinases-1 or -2. Overexpression of I-kappaBalpha inhibited collagenolytic and beta-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-kappaB. Because the inhibition of NF-kappaB reduces proteolytic activity, it appears to be an attractive pharmacological target in unstable atheromas.
Chase
Alexander J
AJ
University of Bristol, Bristol Heart Institute, Bristol, UK.
Bond
Mark
M
Crook
Martin F
MF
Newby
Andrew C
AC
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D023201:CD40 Ligand / Q000378:metabolism; D002364:Caseins / Q000378:metabolism; D002454:Cell Differentiation; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D005487:Foam Cells / Q000378:metabolism* / Q000821:virology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D020672:I-kappa B Proteins; D008264:Macrophages / Q000378:metabolism* / Q000821:virology; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D009000:Monocytes / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014407:Tumor Cells, Cultured
D002364:Caseins; D024042:Collagen Type I; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D000072000:NF-KappaB Inhibitor alpha; D023201:CD40 Ligand; D002784:Cholesterol; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1