Free cholesterol-loaded macrophages are an abundant source of tumor necrosis factor-alpha and interleukin-6: model of NF-kappaB- and map kinase-dependent inflammation in advanced atherosclerosis
| Autor: | Yankun, Li, Robert F, Schwabe, Tracie, DeVries-Seimon, Pin Mei, Yao, Marie-Christine, Gerbod-Giannone, Alan R, Tall, Roger J, Davis, Richard, Flavell, David A, Brenner, Ira, Tabas |
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| Rok vydání: | 2005 |
| Předmět: |
Protein Folding
Time Factors Arteriosclerosis MAP Kinase Signaling System Immunoblotting Enzyme-Linked Immunosorbent Assay Mice Transgenic Endoplasmic Reticulum Models Biological p38 Mitogen-Activated Protein Kinases Mice Cytosol Animals RNA Messenger Cell Nucleus Inflammation Mitogen-Activated Protein Kinase 1 Mice Inbred BALB C Mitogen-Activated Protein Kinase 3 Interleukin-6 Reverse Transcriptase Polymerase Chain Reaction Tumor Necrosis Factor-alpha Macrophages NF-kappa B Biological Transport Enzyme Activation Mice Inbred C57BL Cholesterol Cytokines Female Signal Transduction |
| Zdroj: | The Journal of biological chemistry. 280(23) |
| ISSN: | 0021-9258 |
| Popis: | 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 IkappaB kinase/NF-kappaB pathway as well as activation of MKK3/p38, Erk1/2, and JNK1/2 mitogen-activated protein kinases (MAPK). Activation of IkappaB 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 IkappaB kinase/NF-kappaB 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. |
| Databáze: | OpenAIRE |
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