Oxidized-1-palmitoyl-2-arachidonoyl-sn-glycero-2-phosphorylcholine (OxPAPC), a component of minimally modified low-density lipoprotein (mm-LDL), found in atherosclerotic lesions and other sites of chronic inflammation, induces endothelial cells (EC) to synthesize chemotactic factors, such as interleukin-8 (IL-8). In this study, we provide evidence that OxPAPC paradoxically depletes endothelial caveolae cholesterol, causing caveolin-1 internalization from the plasma membrane to the ER/Golgi, and activates SREBP (Sterol Response Element Binding Protein). Cholesterol loading reverses these effects. OxPAPC-induced SREBP activation occurs as early as 1 hour after treatment and is sustained for at least 8 hours. This activation results in increased transcription of SREBP target genes, LDL receptor and HMG-CoA synthase. Furthermore, cholesterol depletion and SREBP activation play a role in the induction of IL-8 transcription by OxPAPC. Cholesterol depletion by methyl-β-cyclodextran (MBCD) dose-dependently induces IL-8 synthesis. Additionally, cholesterol loading of EC by cholesterol-cyclodextran complex inhibits OxPAPC induction of IL-8. These observations suggest that changes in caveolae cholesterol level can modulate IL-8 synthesis in EC. Interestingly, though IL-8 has been not previously identified as a classic SREBP target gene, we demonstrate using electrophoretic mobility shift assay that SREBP binds to the IL-8 promoter. The in vivo importance of endothelial SREBP activation in atherosclerosis is further suggested by our observation that endothelial cell nuclei stain strongly for SREBP in inflammatory areas of human atherosclerotic lesions. The current studies propose a novel role for endothelial SREBP activation in IL-8 synthesis by oxidized phospholipids and suggest a potential role for SREBP activation in other inflammatory processes where phospholipid oxidation products accumulate.