Enzymatically modified nonoxidized low-density lipoprotein induces interleukin-8 in human endothelial cells: Role of free fatty acids

Background - Treatment of low-density lipoprotein (LDL) with a protease and cholesterolesterase transforms the lipoprotein to an entity that resembles lipoprotein particles in atherosclerotic lesions, which have a high content of free cholesterol, reflecting extensive de-esterification in the intima. Because de-esterification would occur beneath the endothelium, we examined the effects of enzymatically modified LDL (E-LDL) on cultured endothelial cells. Methods and Results - Incubation of endothelial cells with E-LDL provoked selective accumulation of interleukin (IL)-8 mRNA and production of the cytokine. Chemical analyses and depletion experiments indicated that the effect was caused by the presence of free fatty acids in the altered lipoprotein. Reconstitution studies demonstrated that the oleic and linoleic acids associated with E-LDL are particularly effective IL-8 inducers. The effects of E-LDL on endothelial cells could be abrogated with albumin. Conclusion - IL-8 is required for rolling monocytes to adhere firmly to the endothelium; thus, the findings reveal a link between subendothelial entrapment of LDL, cleavage of cholesterol esters, and monocyte recruitment into the lesion.