Oxidized low density lipoproteins (oxLDL) (0.5-50 micrograms/ml) generated from 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 compared to native LDL after a 2-h incubation with macrophage-derived foam cells isolated from the balloon-injured arteries of cholesterol-fed rabbits. Northern blot analyses confirmed that there was also an increase in the mRNA for IL-1 alpha and IL-beta in response to oxLDL in the isolated foam cells. The stimulation of IL-1 expression and production was not due to the contamination of the oxLDL preparations with endotoxin as neither the amount of endotoxin found to be associated with the lipoproteins nor amounts up to 1 ng/ml stimulated IL-1 alpha production to the same degree as oxLDL. Neither oxidized beta-very low density lipoprotein (VLDL) nor oxidized high density lipoprotein (HDL) stimulated IL-1 alpha production by the foam cells. Furthermore, acetyl-LDL had a very limited stimulatory effect, but other known ligands of the scavenger receptor such as maleylated-BSA, polyinosinic acid, and fucoidin elicited maximal IL-1 alpha responses. Fractionation of the oxLDL into lipid- and protein-soluble fractions showed that there was some stimulatory activity in the lipid phase but that known products of lipid peroxidation such as 9- and 13-HODE had no effect when added independently of lipoproteins. When added in combination with native LDL, only 13-HODE stimulated IL-1 alpha production. The delipidated apolipoprotein fragments of oxLDL that had been solubilized in beta-octylglucoside stimulated the production of IL-1 alpha by the foam cells to a greater degree than the lipid extract, while reductively methylated oxLDL did not. These data suggest that interactions of components of both the lipid- and protein-soluble fractions of oxLDL with scavenger receptors or potentially with surface proteins that bind oxLDL may induce production of IL-1 by arterial macrophages.