Interleukin-8 Mediates Downregulation of Tissue Inhibitor of Metalloproteinase-1 Expression in Cholesterol-Loaded Human Macrophages

  • Martine Moreau
    From Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 321 “Lipoproteins and Atherogenesis” (M.M., L.P., M.J.C., M.R.); Service d’Anatomo-Pathologie, Hôpital de la Pitié-Salpêtrière (I.B.); and Institut Federatif de Recherche sur la Physiopathologie et Génétique Cardiovasculaire, Hôpital de la Pitié-Salpêtrière, Université Pierre et Marie Curie (M.M., I.B., L.P., E.N., J.C., M.R.), Paris, France.
  • Isabelle Brocheriou
    From Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 321 “Lipoproteins and Atherogenesis” (M.M., L.P., M.J.C., M.R.); Service d’Anatomo-Pathologie, Hôpital de la Pitié-Salpêtrière (I.B.); and Institut Federatif de Recherche sur la Physiopathologie et Génétique Cardiovasculaire, Hôpital de la Pitié-Salpêtrière, Université Pierre et Marie Curie (M.M., I.B., L.P., E.N., J.C., M.R.), Paris, France.
  • Laure Petit
    From Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 321 “Lipoproteins and Atherogenesis” (M.M., L.P., M.J.C., M.R.); Service d’Anatomo-Pathologie, Hôpital de la Pitié-Salpêtrière (I.B.); and Institut Federatif de Recherche sur la Physiopathologie et Génétique Cardiovasculaire, Hôpital de la Pitié-Salpêtrière, Université Pierre et Marie Curie (M.M., I.B., L.P., E.N., J.C., M.R.), Paris, France.
  • Ewa Ninio
    From Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 321 “Lipoproteins and Atherogenesis” (M.M., L.P., M.J.C., M.R.); Service d’Anatomo-Pathologie, Hôpital de la Pitié-Salpêtrière (I.B.); and Institut Federatif de Recherche sur la Physiopathologie et Génétique Cardiovasculaire, Hôpital de la Pitié-Salpêtrière, Université Pierre et Marie Curie (M.M., I.B., L.P., E.N., J.C., M.R.), Paris, France.
  • M. John Chapman
    From Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 321 “Lipoproteins and Atherogenesis” (M.M., L.P., M.J.C., M.R.); Service d’Anatomo-Pathologie, Hôpital de la Pitié-Salpêtrière (I.B.); and Institut Federatif de Recherche sur la Physiopathologie et Génétique Cardiovasculaire, Hôpital de la Pitié-Salpêtrière, Université Pierre et Marie Curie (M.M., I.B., L.P., E.N., J.C., M.R.), Paris, France.
  • Mustapha Rouis
    From Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 321 “Lipoproteins and Atherogenesis” (M.M., L.P., M.J.C., M.R.); Service d’Anatomo-Pathologie, Hôpital de la Pitié-Salpêtrière (I.B.); and Institut Federatif de Recherche sur la Physiopathologie et Génétique Cardiovasculaire, Hôpital de la Pitié-Salpêtrière, Université Pierre et Marie Curie (M.M., I.B., L.P., E.N., J.C., M.R.), Paris, France.

書誌事項

タイトル別名
  • Relevance to Stability of Atherosclerotic Plaque

抄録

<jats:p> <jats:italic>Background</jats:italic> —The accumulation of macrophage-derived foam cells in atherosclerotic lesions correlates with increased local release of matrix-degrading metalloproteinases (MMPs) and a thin fibrous cap. The activity of these enzymes is controlled by specific tissue inhibitors of metalloproteinases (TIMPs). </jats:p> <jats:p> <jats:italic>Methods and Results</jats:italic> —Because oxidized low-density lipoprotein (OxLDL) modulates gene expression, we investigated the effect of these particles on the levels of MMP-1, MMP-3, MMP-9, TIMP-1, and TIMP-2 in the culture media of human monocyte-derived macrophages. OxLDL but not native LDL or high-density lipoprotein reduced the level of TIMP-1 in a dose-dependent manner with maximal effect (60% of control) at ≈100 μg protein/mL. In addition, Northern blotting revealed marked reduction in the abundance of TIMP-1 mRNA in OxLDL-treated cells. Evaluation of the effect of oxysterol components of OxLDL on TIMP-1 production revealed that 25-hydroxycholesterol (1 μg/mL) was the most potent inhibitor (≈30% of control). Such inhibition was partially mediated by interleukin (IL)-8. Indeed, IL-8 (2.5 ng/mL) induced maximal inhibition of TIMP-1 accumulation (30% of control) in 4 of 6 cell preparations. In addition, the inhibitory effect of OxLDL-treated cells in the presence of an anti–IL-8 neutralizing antibody was partially reversed. </jats:p> <jats:p> <jats:italic>Conclusions</jats:italic> —Immunohistochemical analyses of human atherosclerotic plaques revealed the expression of TIMP-1 in some but not all macrophage-rich and IL-8–rich areas. Therefore, IL-8 may play a potential atherogenic role by inhibiting local TIMP-1 expression, thereby leading to an imbalance between MMPs and TIMPs at focal sites in the atherosclerotic plaque. </jats:p>

収録刊行物

  • Circulation

    Circulation 99 (3), 420-426, 1999-01-26

    Ovid Technologies (Wolters Kluwer Health)

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