title: Regulation of matrix metalloproteinase expression in human vascular smooth muscle cells by T lymphocytes: a role for CD40 signaling in plaque rupture?
abstract: Physical disruption of an atheromatous lesion often underlies acute coronary syndromes. Matrix-degrading enzymes, eg, matrix metalloproteinases (MMPs), may cause loss in mechanical integrity of plaque tissue that favors rupture. T lymphocytes accumulate at sites where atheromata rupture, but the mechanisms by which these immune cells may contribute to plaque destabilization are unknown. This study tested the hypothesis that the T-lymphocyte surface molecule CD40 ligand (CD40L), recently localized in atherosclerotic plaques, regulates the expression of MMPs in human vascular smooth muscle cells (SMCs), the most numerous cell type in arteries. We report here that stimulated human T lymphocytes induced the expression of the matrix-degrading enzymes, ie, interstitial collagenase (MMP-1), stromelysin (MMP-3), gelatinase B (MMP-9), and activated gelatinase A (MMP-2), in human vascular SMCs by cell contact via CD40 ligation, as demonstrated by Western blot analysis, zymography, and antibody neutralization. Recombinant human CD40L (rCD40L) induced de novo synthesis of MMP-1, MMP-3, and MMP-9 on vascular SMCs and stimulated the expression of these enzymes to a greater extent than did maximally effective concentrations of tumor necrosis factor-alpha or interleukin-1beta, established agonists of MMP expression. Interferon gamma, another T-lymphocyte- derived cytokine, inhibited the induction of MMPs by rCD40L. Immunohistochemical analysis of human coronary atheromata colocalized MMP-1 and MMP-3 with CD40-positive SMCs. These results demonstrated that CD40 ligand, expressed on T lymphocytes, promoted the expression of matrix-degrading enzymes in vascular SMCs and thus established a new pathway of immune-modulated destabilization in human atheromata.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass 02115, USA.
authors.forename: U
authors.initials: U
authors.lastname: Schönbeck
authors.forename: F
authors.initials: F
authors.lastname: Mach
authors.forename: G K
authors.initials: GK
authors.lastname: Sukhova
authors.forename: C
authors.initials: C
authors.lastname: Murphy
authors.forename: J Y
authors.initials: JY
authors.lastname: Bonnefoy
authors.forename: R P
authors.initials: RP
authors.lastname: Fabunmi
authors.forename: P
authors.initials: P
authors.lastname: Libby
mesh_terms: D001161:Arteriosclerosis / Q000150:complications / Q000201:enzymology* / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D019013:CD40 Antigens / Q000378:metabolism; D002450:Cell Communication; D002478:Cells, Cultured; D017364:Collagenases / Q000096:biosynthesis; D016207:Cytokines / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D018093:Gelatinases / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation; D020781:Matrix Metalloproteinase 1; D020778:Matrix Metalloproteinase 2; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000201:enzymology*; D009203:Myocardial Infarction / Q000209:etiology; D012422:Rupture, Spontaneous; D015398:Signal Transduction
chemical_list: D019013:CD40 Antigens; D016207:Cytokines; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1