Interleukin-10 facilitates both cholesterol uptake and efflux in macrophages.
Foam cell formation is a hallmark event during atherosclerosis. The current paradigm is that lipid uptake by scavenger receptor in macrophages initiates the chronic proinflammatory cascade and necrosis core formation that characterize atherosclerosis. We report here that a cytokine considered to be anti-atherogenic, interleukin-10 (IL10), promotes cholesterol uptake from modified lipoproteins in macrophages and its transformation into foam cells by increasing the expression of scavenger receptor CD36 and scavenger receptor A. Although uptake of modified lipoproteins is considered proatherogenic, we found that IL10 also increases cholesterol efflux from macrophages to protect against toxicity of free cholesterol accumulation in the cell. This process was PPARgamma-dependent and was mediated through up-regulation of ABCA1 (ATP-binding cassette transporter A1) protein expression. Importantly, expression of inflammatory molecules, such as tumor necrosis factor-alpha, intercellular adhesion molecule-1, and MMP9 as well as apoptosis were dramatically suppressed in lipid-laden foam cells treated with IL10. The notion that IL10 can mediate both the uptake of cholesterol from modified lipoproteins and the efflux of stored cholesterol suggests that the process of foam cell formation is not necessarily detrimental as long as mechanisms of cholesterol efflux and transfer to an exogenous acceptor are functioning robustly. Our results present a comprehensive antiatherogenic role of IL10 in macrophages, including enhanced disposal of harmful lipoproteins, inhibition of inflammatory molecules, and reduced apoptosis.
Han
Xinbing
X
Vascular Medicine Research Unit, Brigham Women's Hospital, Harvard Medical School, Cambridge, Massachusetts 02139, USA.
Kitamoto
Shiro
S
Lian
Qingyu
Q
Boisvert
William A
WA
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism*; D018955:CD36 Antigens / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D016753:Interleukin-10 / Q000378:metabolism*; D008055:Lipids / Q000737:chemistry; D008074:Lipoproteins / Q000737:chemistry; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D015854:Up-Regulation
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D018955:CD36 Antigens; D016207:Cytokines; D008055:Lipids; D008074:Lipoproteins; D016753:Interleukin-10; D002784:Cholesterol; D053148:Caspase 3