Oxidized LDL Induces Monocytic Cell Expression of Interleukin-8, a Chemokine With T-Lymphocyte Chemotactic Activity

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Abstract T lymphocytes, macrophages, and oxidized lowdensity lipoprotein (Ox-LDL) are collocalized in early atherosclerotic lesions. Using a low-endotoxin in vitro system, we observed that Ox-LDL but not native LDL induced the production, by both freshly adherent human peripheral blood monocytes and human monocytic THP-1 cells, of the α chemokine interleukin (IL)-8, a potent chemoattractant for T lymphocytes. Marked IL-8 induction by Ox-LDL did not require IL-1β generation in THP-1 cells. Ox-LDL-induced chemokine production was selective, as Ox-LDL did not stimulate the production by THP-1 cells of the T-lymphocyte chemotactic β chemokine macrophage inflammatory protein (MlP)-la. IL-8 induction increased in proportion to the extent of oxidation of LDL as measured by the content of lipid oxidation end products.To identify potentially active components of Ox-LDL, we tested malondialdehyde, an arachidonate- derived lipid oxidation product, and 9-hydroxyoctadecadienoic acid, an oxidation product of linoleate, the major polyunsaturated fatty acid in LDL, and observed that they Induced IL-8 generation in the absence of Ox-LDL. Furthermore, when most free lipid oxidation products were removed from Ox-LDL by dialysis, some IL-8-inducing activity was released into the dialysate. However, the major IL-8-inducing activity was not dialyzable. To address the nature of the LDL particle modification required to induce IL-8, acetylated or malondialdehyde-trcated native LDL particles were monitored for activity. Neither procedure rendered LDL capable of inducing IL-8. However, phospholipase A$-treated LDL induced THP-1 cell expression of IL-8. Thus, Ox-LDL induced a chemokine in monocytic THP-1 cells by a mechanism that did not absolutely require IL-1/3, appeared to be predominantly mediated by particle-associated and nondiffusible end products of lipid degradation, and could be reproduced by phospholipase A2 treatment of LDL.

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