Oxidized LDL induces monocytic cell expression of interleukin-8, a chemokine with T-lymphocyte chemotactic activity.
T lymphocytes, macrophages, and oxidized low-density 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 alpha chemokine interleukin (IL)-8, a potent chemoattractant for T lymphocytes. Marked IL-8 induction by Ox-LDL did not require IL-1 beta 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 beta chemokine macrophage inflammatory protein (MIP)-1 alpha. 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-treated native LDL particles were monitored for activity. Neither procedure rendered LDL capable of inducing IL-8. However, phospholipase A2-treated LDL induced THP-1 cell expression of IL-8.(ABSTRACT TRUNCATED AT 250 WORDS)
Terkeltaub
R
R
VA Medical Center, San Diego, CA 92161.
Banka
C L
CL
Solan
J
J
Santoro
D
D
Brand
K
K
Curtiss
L K
LK
D000107:Acetylation; D002634:Chemotaxis, Leukocyte; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis*; D007951:Leukemia, Myeloid; D008041:Linoleic Acids / Q000494:pharmacology; D044243:Linoleic Acids, Conjugated; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008315:Malondialdehyde / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D010741:Phospholipases A / Q000494:pharmacology; D054467:Phospholipases A2; D013601:T-Lymphocytes / Q000502:physiology*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014407:Tumor Cells, Cultured
D007375:Interleukin-1; D016209:Interleukin-8; D008041:Linoleic Acids; D044243:Linoleic Acids, Conjugated; D008077:Lipoproteins, LDL; D017392:Thiobarbituric Acid Reactive Substances; C024347:9-hydroxy-10,12-octadecadienoic acid; D008315:Malondialdehyde; D010741:Phospholipases A; D054467:Phospholipases A2