Oxidized LDL induces monocytic cell expression of interleukin-8, a chemokine with T-lymphocyte chemotactic activity.

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 a chemokine interleukin (IL)-8, a potent chemoattractant for T lymphocytes. Marked IL-8 induction by Ox-LDL did not require IL-10 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 f) 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 A 2 treatment of LDL. The Ox-LDL-induced generation from monocyte/macrophages of selected chemokines that chemoattract T lymphocytes may contribute to atherogenic and inflammation-regulating properties of Ox-LDL {ArterioscUr Thromb. 1994;14:47-53.) Key Words • oxidized LDL • chemokines • interleukin-8 • macrophage inflammatory protein-la • interleukin-1 • T lymphocytes • atherosclerosis T he cellular components of certain atherosclerotic lesions include T lymphocytes, which are not usually present within the normal arterial wall.14 Within early atherosclerotic lesions (ie, intimal thickening and fatty streaks), T cells and macrophages are collocalized in significant numbers.5 T lymphocytes also comprise up to 20% of the cells in the fibrous cap.

Prostaglandin E2 Suppresses Chemokine Production in Human Macrophages through the EP4 Receptor

“…Thus, chemokines play a pivotal role in the development and complication of atheroma. Modified LDL and pro-inflammatory cytokines such as TNF␣, IL-1␤, IFN␥, or CD40 ligand induce chemokine expression in cells found in atheroma, such as EC, SMC, and M⌽ (31)(32)(33). However, knowledge of potential endogenous inhibitory mechanisms has lagged behind understanding of pro-inflammatory stimuli.…”

“…The cDNA microarray experiments were performed with GF211 cDNA array (Research Genetics, Huntsville, AL) containing 4324 known genes. One microgram of total RNA from each experimental condition was used to synthesize 33 P-labeled probes. The hybridization, the data collection, and the data normalization were performed as described previously (16).…”

Oxidized LDL modulates activation of NFκB in mononuclear phagocytes by altering the degradation of IκBs

“…oxLDL has been demonstrated to modulate the expression of inflammatory cytokines in cell types present in the vascular wall and this activity is believed to be an important mechanistic feature of its pathophysiological action [5][6][7][8][9][10][11][12]. It is interesting to note that oxLDL can modulate inflammatory gene expression in both positive and negative fashion.…”

“…Among the variables that determine the nature of the effect are the cell type and the magnitude of LDL oxidation. Although minimally modified LDL appears to promote inflammatory responses in leukocytes, endothelial cells, and smooth muscle cells [6,7,9,11,13), extensively oxidized LDL, likely to be encountered in older lesions, has been found to suppress the expression of multiple gene products in stimulated macrophages [8,10,14]. Modulation of macrophage inflammatory cytokine gene expression by oxLDL requires pretreatment and the effects of oxLDL on macrophages vary both with the stimulus and the gene under examination [15,16].…”

Low-Density Lipoprotein Modified by Macrophage-Derived Lysosomal Hydrolases Induces Expression and Secretion of IL-8 Via p38 MAPK and NF-κB by Human Monocyte-Derived Macrophages

“…3 Although low-density lipoprotein (LDL) modifications are thought to be a prerequisite for atherosclerosis, the actual types of modifications that drive atherogenesis in the human arterial intima are currently not known. LDL particles undergo oxidative modification to some extent in arterial wall, 4 and oxidized LDL induces expression of IL-8 in monocytes 5 and macrophages 2 in vitro. In addition, there is evidence for enzymatic modification of LDL in the arterial intima, 6 leading to the generation of morphologically modified unesterified cholesterol-rich particles with proinflammatory properties, such as secretion of IL-8 from endothelial cells.…”