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J. Biol. Chem., Vol. 280, Issue 23, 21763-21772, June 10, 2005
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Free Cholesterol-loaded Macrophages Are an Abundant Source of Tumor Necrosis Factor-
and Interleukin-6
MODEL OF NF-
B- AND MAP KINASE-DEPENDENT INFLAMMATION IN ADVANCED ATHEROSCLEROSIS*
||**
From the
Departments of Medicine and ||Anatomy and Cell Biology and Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, the Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, and the ¶Section of Immunobiology, Yale University School of Medicine and Howard Hughes Medical Institute, New Haven, Connecticut 06520
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-
(TNF-) and interleukin-6 (IL-6). The increases in TNF- and IL-6 mRNA and protein were mediated by FC-induced activation of the IB kinase/NF-B pathway as well as activation of MKK3/p38, Erk1/2, and JNK1/2 mitogen-activated protein kinases (MAPK). Activation of IB kinase and JNK1/2 was needed for the induction of both cytokines. However, MKK3/p38 signaling was specifically involved in TNF- 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 IB kinase/NF-B and for the induction of TNF-. 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.
Received for publication, February 15, 2005 , and in revised form, April 11, 2005.
* This work was supported by National Institutes of Health Grants HL54591 and HL75662 (to I. T.), American Heart Association Scientist Development Grant 0435364T (to Y. L.), American Heart Association Post-doctoral Training Grant 04255805T (to T. D.-S.), and a Research Scholar Award from the American Gastroenterological Association and Procter & Gamble (to R. F. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
** To whom correspondence should be addressed: Dept. of Medicine, Columbia University, 630 West 168th St., New York, NY 10032. Tel.: 212-305-9430; Fax: 212-305-4834; E-mail: iat1{at}columbia.edu.
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