MULTIPLE LIPID OXIDATION-PRODUCTS IN LOW-DENSITY LIPOPROTEINS INDUCE INTERLEUKIN-1-BETA RELEASE FROM HUMAN BLOOD MONONUCLEAR-CELLS

Oxidized low density lipoproteins (LDL) induce the release of interleu kin-1 beta (IL-1 beta) from human peripheral blood mononuclear cells, a process that may contribute to atherogenesis. While 9-hydroxyoctadec adienoic acid (9-HODE) is a constituent of oxidized LDL and can by its elf induce IL-1 beta release, its potency relative to oxidized LDL sug gested that other components of modified LDL may also contribute to th is phenomenon. In this study, LDL of varying oxidation states were pre pared by altering the Cu2+ to LDL ratio and/or the length of oxidation . The oxidation status of LDL was measured as thiobarbituric acid reac tive substances (TBARS), electrophoretic mobility in agarose gels, and the content of 9- and 13-HODE. High CU2+ to LDL,ties promoted extensi ve TBARS formation and these LDL were the most potent activators of IL -1 beta release, although LDL with TBARS greater than 50 nmol/mg prote in were cytotoxic and IL-1 beta release was diminished. An inverse cor relation between HODE content and TBARS was found indicating lipid-der ived aldehydes also contribute to IL-1 beta release by oxidized LDL. A ccordingly dialysis of oxidized LDL removed nearly all aldehydes and r endered 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 rel ease while their saturated homologues had no effect. The predominant a ldehyde in Cu2+-oxidized LDL was hexanal, with the unsaturated aldehyd es 2,4-heptadienal, 2-octenal, and 2,4-decadienal also being present. These data indicate that multiple, lipid-derived species exist in oxid ized LDL that can contribute to the release of IL-1 beta.