Free cholesterol-loaded macrophages are an abundant source of tumor necrosis factor-α and interleukin-6

被引:353
|
作者
Li, YK
Schwabe, RF
DeVries-Seimon, T
Yao, PM
Gerbod-Giannone, MC
Tall, AR
Davis, RJ
Flavell, R
Brenner, DA
Tabas, I
机构
[1] Columbia Univ, Dept Med, New York, NY 10032 USA
[2] Columbia Univ, Dept Anat & Cell Biol, New York, NY 10032 USA
[3] Columbia Univ, Dept Physiol & Cellular Biophys, New York, NY 10032 USA
[4] Univ Massachusetts, Sch Med, Howard Hughes Med Inst, Worcester, MA 01605 USA
[5] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA
[6] Yale Univ, Sch Med, Immunobiol Sect, New Haven, CT 06520 USA
[7] Howard Hughes Med Inst, New Haven, CT 06510 USA
关键词
D O I
10.1074/jbc.M501759200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Two key features of atherosclerotic plaques that precipitate acute atherothrombotic vascular occlusion ("vulnerable plaques") are abundant inflammatory mediators and macrophages with excess unesterified, or "free," cholesterol (FC). Herein we show that FC accumulation in macrophages leads to the induction and secretion of two inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). The increases in TNF-alpha and IL-6 mRNA and protein were mediated by FC-induced activation of the I kappa B kinase/NF-kappa B pathway as well as activation of MKK3/p38, Erk1/2, and JNK1/2 mitogen-activated protein kinases (MAPK). Activation of I kappa B kinase and JNK1/2 was needed for the induction of both cytokines. However, MKK3/p38 signaling was specifically involved in TNF-alpha induction, and Erk1/2 signaling was required for IL-6. Most interestingly, activation of all of the signaling pathways and induction of both cytokines required cholesterol trafficking to the endoplasmic reticulum (ER). The CHOP branch of the unfolded protein response, an ER stress pathway, was required for Erk1/2 activation and IL-6 induction. In contrast, one or more other ER-related pathways were responsible for activation of p38, JNK1/2, and I kappa B kinase/NF-kappa B and for the induction of TNF-alpha. These data suggest a novel scenario in which cytokines are induced in macrophages by endogenous cellular events triggered by excess ER cholesterol rather than by exogenous immune cell mediators. Moreover, this model may help explain the relationship between FC accumulation and inflammation in vulnerable plaques.
引用
收藏
页码:21763 / 21772
页数:10
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