Interleukin-4 augments acetylated LDL-induced cholesterol esterification in macrophages

Activated subpopulations of lymphocytes and mast cells have been detected i n atherosclerotic lesions, Interleukin-4 (IL-4) is a prominent cytokine rel eased during activation of both cell types and its transcripts ha c-e been detected in both human and mouse atherosclerotic lesions. To define whether this local release of LU influences macrophage lipid metabolism, we examin ed the effects of this cytokine on intracellular cholesterol esterification during incubation with modified lo tv density lipoprotein (LDL), EU greatl y augmented cholesterol esterification induced by acetylated LBL (AcLDL) in both mouse peritoneal macrophages and the murine macrophage cell line, J77 4. This augmentation was maximal at a concentration of 1 ng/ml after incuba tion for 48 h. This was not a generalized effect on lipoprotein metabolism as IL-4 had no effect on cholesterol esterification in the presence of eith er LDL or beta-VLDL. Determination of binding isotherms demonstrated that I L-4 increased the number of cell surface binding sites for AcLDL. The IL-4- augmented AcLDL-induced cholesterol esterification was attenuated by the sc avenger receptor class A (SR-A) antagonist, fucoidan, and the anti-mouse SR -A monoclonal antibody 2F8. These data, combined with the known receptor sp ecificity of AcLDL interactions, imply a role of SR-A in the IU induced res ponses. Two cytokines that have been demonstrated previously to down-regula te SR-A TNF-alpha and TGF-beta, antagonized the IL-4-induced augmentation o f cholesterol esterification. Therefore, local release of IL-4 within ather osclerotic lesions could ha-ve a profound effect on macrophage lipid metabo lism and the subsequent atherogenic process.