Multiple lipid oxidation products in low density lipoproteins induce interleukin-1 beta release from human blood...

Oxidized low density lipoproteins (LDL) induce the release of interleukin-1 beta (IL-1 beta) from human peripheral blood mononuclear cells, a process that may contribute to atherogenesis. While 9-hydroxyoctadecadienoic acid (9-HODE) is a constituent of oxidized LDL and can by itself induce IL-1 beta release, its potency relative to oxidized LDL suggested that other components of modified LDL may also contribute to this phenomenon. In this study, LDL of varying oxidation states were prepared by altering the Cu2+ to LDL ratio and/or the length of oxidation. The oxidation status of LDL was measured as thiobarbituric acid reactive substances (TBARS), electrophoretic mobility in agarose gels, and the content of 9- and 13-HODE. High Cu2+ to LDL ratios promoted extensive TBARS formation and these LDL were the most potent activators of IL-1 beta release, although LDL with TBARS greater than 50 nmol/mg protein were cytotoxic and IL-1 beta release was diminished. An inverse correlation between HODE content and TBARS was found indicating lipid-derived aldehydes also contribute to IL-1 beta release by oxidized LDL. Accordingly, dialysis of oxidized LDL removed nearly all aldehydes and rendered the LDL unable to induce IL-1 beta release. The alkenals 2,4-decadienal and 2-octenal were tested and shown to induce IL-1 beta release while their saturated homologues had no effect. The predominant aldehyde in Cu(2+)-oxidized LDL was hexanal, with the unsaturated aldehydes 2,4-heptadienal, 2-octenal, and 2,4-decadienal also being present. These data indicate that multiple, lipid-derived species exist in oxidized LDL that can contribute to the release of IL-1 beta.