COMPONENTS OF THE PROTEIN-FRACTION OF OXIDIZED LOW-DENSITY-LIPOPROTEIN STIMULATE INTERLEUKIN-1-ALPHA PRODUCTION BY RABBIT ARTERIAL MACROPHAGE-DERIVED FOAM CELLS

Oxidized low density lipoproteins (oxLDL) (0.5-50 mu g/ml) generated f rom both rabbit and human LDL stimulated the production of interleukin -1 alpha (IL-1 alpha) by as much as 2- and 6-fold, respectively, as co mpared to native LDL after a 2-h incubation with macrophage-derived fo am cells isolated from the balloon-injured arteries of cholesterol-fed rabbits. Northern blot analyses confirmed that there was also an incr ease in the mRNA for IL-1 alpha and IL-beta in response to oxLDL in th e isolated foam cells. The stimulation of IL-1 expression and producti on was not due to the contamination of the oxLDL preparations with end otoxin as neither the amount of endotoxin found to be associated with the lipoproteins nor amounts up to 1 ng/ml stimulated IL-1 alpha produ ction to the same degree as oxLDL. Neither oxidized beta-very low dens ity lipoprotein (VLDL) nor oxidized high density lipoprotein (HDL) sti mulated IL-1 alpha production by the foam cells. Furthermore, acetyl-L DL had a very limited stimulatory effect, but other known ligands of t he scavenger receptor such as maleylated-BSA, polyinosinic acid, and f ucoidin elicited maximal IL-1 alpha responses. Fractionation of the ox LDL into lipid- and protein-soluble fractions showed that there was so me stimulatory activity in the lipid phase but that known products of lipid peroxidation such as 9- and 13-HODE had no effect when added ind ependently of lipoproteins. When added in combination with native LDL, only 13-HODE stimulated IL-1 alpha production. The delipidated apolip oprotein fragments of oxLDL that had been solubilized in beta-octylglu coside stimulated the production of IL-1 alpha by the foam cells to a greater degree than the lipid extract, while reductively methylated ox LDL did not. These data suggest that interactions of components of bot h the lipid- and protein-soluble fractions of oxLDL with scavenger rec eptors or potentially with surface proteins that bind oxLDL may induce production of IL-1 by arterial macrophages.