Interleukin-4 augments acetylated LDL-induced cholesterol esterification in macrophages.
Activated subpopulations of lymphocytes and mast cells have been detected in atherosclerotic lesions. Interleukin-4 (IL-4) is a prominent cytokine released during activation of both cell types and its transcripts have been detected in both human and mouse atherosclerotic lesions. To define whether this local release of IL-4 influences macrophage lipid metabolism, we examined the effects of this cytokine on intracellular cholesterol esterification during incubation with modified low density lipoprotein (LDL). IL-4 greatly augmented cholesterol esterification induced by acetylated LDL (AcLDL) in both mouse peritoneal macrophages and the murine macrophage cell line, J774. This augmentation was maximal at a concentration of 1 ng/ml after incubation 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 either LDL or beta-VLDL. Determination of binding isotherms demonstrated that IL-4 increased the number of cell surface binding sites for AcLDL. The IL-4-augmented AcLDL-induced cholesterol esterification was attenuated by the scavenger receptor class A (SR-A) antagonist, fucoidan, and the anti-mouse SR-A monoclonal antibody, 2F8. These data, combined with the known receptor specificity of AcLDL interactions, imply a role of SR-A in the IL-4 induced responses. Two cytokines that have been demonstrated previously to down-regulate SR-A, TNF-alpha and TGF-beta, antagonized the IL-4-induced augmentation of cholesterol esterification. Therefore, local release of IL-4 within atherosclerotic lesions could have a profound effect on macrophage lipid metabolism and the subsequent atherogenic process.
Cornicelli
J A
JA
Department of Vascular Diseases, Parke Davis, 2800 Plymouth Road, Ann Arbor, MI 48106, USA.
Butteiger
D
D
Rateri
D L
DL
Welch
K
K
Daugherty
A
A
D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D004951:Esterification; D015847:Interleukin-4 / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000502:physiology*; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D008297:Male; D051379:Mice
D008077:Lipoproteins, LDL; C032629:acetyl-LDL; D015847:Interleukin-4; D002784:Cholesterol