Interleukin-10 Facilitates Both Cholesterol Uptake and Efflux in Macrophages

Xinbing Han,Shiro Kitamoto,Qingyu Lian,William A Boisvert

doi:10.1074/jbc.m109.040899

Xinbing Han, Shiro Kitamoto + Show 2 more

Open Access

https://doi.org/10.1074/jbc.m109.040899

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Abstract

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.

Highlights

Internalization of modified LDL, which has long been considered one of the requisite initiating events in atherogenesis [2,3,4]
The macrophages were treated with AcLDL in the presence or absence of IL10; in another model, foam cells were generated by pretreatment with AcLDL for 36 – 48 h and treated with or without IL10
The first model is especially useful to study the role of IL10 in foam cell formation, whereas the latter was adopted to assess the role of IL10 in modulating a variety of functions in foam cells relevant to atherosclerosis

Summary

Introduction

Internalization of modified LDL, which has long been considered one of the requisite initiating events in atherogenesis [2,3,4]. IL10 Induces Cholesterol Efflux through the PPAR␥-ABCA1 terol efflux by IL10 treatment occurs through at least two Pathway—We asked if IL10 plays a role in reverse choles- mechanisms: 1) increase in CD36 expression, which facilitates terol transport, especially in the presence of a cholesterol the uptake of modified LDL and leads to lipid accumulation acceptor, such as lipid-free apoA1.

Results

Conclusion