(Circulation. 1999;99:420-426.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Interleukin-8 Mediates Downregulation of Tissue Inhibitor of Metalloproteinase-1 Expression in Cholesterol-Loaded Human Macrophages
Relevance to Stability of Atherosclerotic Plaque
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.
Correspondence to Mustapha Rouis, PhD, INSERM U-321 Pavillon Benjamin Delessert, Hôpital de la Pitié-Salpêtrière, 83 Bd de l' Hôpital, 75651 Paris Cedex 13, France.. E-mail rouis{at}infobiogen.fr
Background—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).
Methods and Results—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.
Conclusions—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.
Key Words: atherosclerosis • lesions • interleukins • lipoproteins • plaque • metalloproteinases tissue inhibitor
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