Crosstalk between LXR and Toll-like Receptor Signaling Mediates Bacterial and Viral Antagonism of Cholesterol Metabolism
| Autor: | Peter Tontonoz, Antonio Castrillo, Genhong Cheng, Sagar A. Vaidya, M E Haberland, Sean B. Joseph, Alan M. Fogelman |
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| Rok vydání: | 2003 |
| Předmět: |
Arteriosclerosis
Receptors Cytoplasmic and Nuclear Receptors Cell Surface Ligands Cell Line Mice Genes Regulator polycyclic compounds Animals Receptors Immunologic Promoter Regions Genetic Liver X receptor Molecular Biology Adaptor Proteins Signal Transducing Liver X Receptors Mice Knockout Toll-like receptor Membrane Glycoproteins Innate immune system biology Effector Macrophages Toll-Like Receptors NF-kappa B Bacterial Infections Cell Biology Orphan Nuclear Receptors Antigens Differentiation Toll-Like Receptor 3 Cell biology DNA-Binding Proteins Mice Inbred C57BL Crosstalk (biology) Cholesterol Gene Expression Regulation Biochemistry Virus Diseases ABCA1 Myeloid Differentiation Factor 88 TLR3 biology.protein ATP-Binding Cassette Transporters Interferon Regulatory Factor-3 lipids (amino acids peptides and proteins) Signal transduction ATP Binding Cassette Transporter 1 Signal Transduction Transcription Factors |
| Zdroj: | Molecular Cell. 12:805-816 |
| ISSN: | 1097-2765 |
| DOI: | 10.1016/s1097-2765(03)00384-8 |
| Popis: | The liver X receptors (LXR) alpha and beta are regulators of cholesterol metabolism and determinants of atherosclerosis susceptibility. Viral and bacterial pathogens have long been suspected to be modulators of atherogenesis; however, mechanisms linking innate immunity to cholesterol metabolism are poorly defined. We demonstrate here that pathogens interfere with macrophage cholesterol metabolism through inhibition of the LXR signaling pathway. Activation of Toll-like receptors (TLR) 3 and 4 by microbial ligands blocks the induction of LXR target genes including ABCA1 in cultured macrophages as well as in aortic tissue in vivo. As a consequence of these transcriptional effects, TLR3/4 ligands strongly inhibit cholesterol efflux from macrophages. Crosstalk between LXR and TLR signaling is mediated by IRF3, a specific effector of TLR3/4 that inhibits the transcriptional activity of LXR on its target promoters. These findings highlight a common mechanism whereby bacterial and viral pathogens may modulate macrophage cholesterol metabolism and cardiovascular disease. |
| Databáze: | OpenAIRE |
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