In atherogenesis, macrophage foam cell formation is modulated by pathways involving both the uptake and efflux of cholesterol. We recently showed that interleukin-10 (IL-10) modulates lipid metabolism by enhancing both uptake and efflux of cholesterol in macrophages. However, the mechanistic details of these properties in vivo have been unclear. Thus, the purpose of this study was to determine whether expression of IL-10 in macrophages would alter susceptibility to atherosclerosis and whether IL-10 exerts its antiatherosclerotic properties by modulating lipid metabolism in macrophages. We utilized a macrophage-specific retroviral vector that allows long-term in vivo expression of IL-10 in macrophages through transplantation of retrovirally transduced bone marrow cells (BMCs). IL-10 expressed by macrophages derived from transduced BMCs inhibited atherosclerosis in LDLR(-/-) mice by reducing cholesteryl ester accumulation in atherosclerotic sites. Experiments with primary macrophages indicated that macrophage source of IL-10 stimulated both the uptake (by up-regulating scavenger receptors) and efflux of cholesterol (by activating the PPARgamma-LXR-ABCA1/ABCG1 pathway), thereby reducing inflammation and apoptosis in atherosclerosis. These findings indicate that BMC-transduced macrophage IL-10 production can act as a strong antiatherogenic agent, and they highlight a novel antiatherosclerotic therapy using a simple, yet effective, stem cell transduction system that facilitates long-term expression of IL-10 in macrophages.

Atherosclerosis is primarily a disorder of lipid metabolism, but there is also a prominent chronic inflammatory component that drives the atherosclerotic lesion progression in the artery wall. During hyperlipidaemic conditions, there is a rapid influx of circulating monocytes into the atherosclerosis-prone areas of the arterial intima. These infiltrated monocytes differentiate into macrophages and take up the atherogenic lipoproteins in the intima of the vessel wall that have been modified within the lesion environment. Interleukin (IL)-10 is a prototypic anti-inflammatory cytokine made primarily by the macrophages and Th2 subtype T lymphocytes. In terms of atherosclerosis its major roles include inhibition of macrophage activation as well as inhibition of matrix metalloproteinase, pro-inflammatory cytokines and cyclooxygenase-2 expression in lipid-loaded and activated macrophage foam cells. Recent discoveries suggest another important role of IL-10 in atherosclerosis: its ability to alter lipid metabolism in macrophages. The current review will highlight the present knowledge on multiple ways in which IL-10 mediates atherosclerosis. As macrophages play a critical role in all stages of atherosclerosis, the review will concentrate on how IL-10 regulates the activities of macrophages that are especially important in the development of atherosclerosis.

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 antiatherogenic, 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 PPAR␥-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-␣, 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.One of the key events in atherosclerosis is the formation of foam cells. Macrophages in the arterial intima take up modified LDL 2 and become cholesteryl ester-laden foam cells. These foam cells are the predominant cell types (ϳ80%) in fatty streak at the early stage of atherosclerosis and play a pivotal role throughout lesion progression and plaque vulnerability (1, 2). Macrophage foam cell formation in atherosclerotic blood vessel intima is mediated by scavenger receptor (SR)-dependent internalization of modified LDL, which has long been considered one of the requisite initiating events in atherogenesis (2-4). The receptors that play the most important role in atherosclerosis include SR class A, types I and II, as well as the SR class B, CD36. These principal receptors are responsible for the uptake of modified LDL that leads to lipid loading in macrophages (5-7).Interleukin-10 (IL10), an anti-inflammatory cytokine, is present within human atherosclerotic plaques (8), primarily in macrophage-rich regions. Data from IL10-deficient mice or IL10-overexpressing mice have implicated a protective role of IL10 during atherosclerosis (9 -12). One of the antiatherogenic properties of IL10 may be its ability to regulate lipid metabolism in macrophages. There is, however, considerable controversy in the literature regarding the exact role that IL10 plays in this process (13-15). Whether IL10 inhibits (13, 15) or enhances foam cell for...