Interleukin-6 Stimulates LDL Receptor Gene Expression via Activation of Sterol-Responsive and Sp1 Binding Elements

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 20; no. 7; pp. 1777 - 1783
• Main Authors: Gierens, Hedi, Nauck, Markus, Roth, Michael, Schinker, Renana, Schürmann, Christine, Scharnagl, Hubert, Neuhaus, Gunther, Wieland, Heinrich, März, Winfried
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01-07-2000; Hagerstown, MD Lippincott
• Subjects: Analysis of the immune response. Humoral and cellular immunity; Biological and medical sciences; Blotting, Northern; CCAAT-Enhancer-Binding Proteins; Cells, Cultured; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Dose-Response Relationship, Drug; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Expression Regulation - drug effects; Humans; Hypercholesterolemia - metabolism; Immunobiology; Interleukin-6 - pharmacology; Iodine Radioisotopes; Liver - cytology; Lymphokines, interleukins ( function, expression); Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Phosphorus Radioisotopes; Promoter Regions, Genetic - physiology; Receptors, LDL - genetics; Receptors, LDL - metabolism; Regulatory factors and their cellular receptors; RNA, Messenger - metabolism; Sp1 Transcription Factor - genetics; Sp1 Transcription Factor - metabolism; Sp3 Transcription Factor; Sterol Regulatory Element Binding Protein 1; Sterol Regulatory Element Binding Protein 2; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic - drug effects; Transcription, Genetic - physiology; Transfection; Interleukin; Cytokine; Lipids; Gene expression; Metabolism; Biological activity; Interleukin 6; Lipoprotein LDL; Binding protein; Regulation(control); Gene; Hepatocyte; Immune system; Biological receptor
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/01.ATV.20.7.1777

Inflammatory or malignant diseases are associated with elevated levels of cytokines and abnormal low density lipoprotein (LDL) cholesterol metabolism. In the acute-phase response to myocardial injury or other trauma or surgery, total and LDL cholesterol levels are markedly decreased. We investigated the effects of the proinflammatory cytokine interleukin (IL)-6 on LDL receptor (LDL-R) function and gene expression in HepG2 cells. IL-6 dose-dependently increased the binding, internalization, and degradation of I-LDL. IL-6–stimulated HepG2 cells revealed increased steady-state levels of LDL-R mRNA. In HepG2 cells transiently transfected with reporter gene constructs harboring the sequence of the LDL-R promoter extending from nucleotide −1563 (or from nucleotide −234) through −58 relative to the translation start site, IL-6 dose-dependently increased promoter activity. In the presence of LDL, a similar relative stimulatory effect of IL-6 was observed. Studies using a reporter plasmid with a functionally disrupted sterol-responsive element (SRE)-1 revealed a reduced stimulatory response to IL-6. In gel-shift assays, nuclear extracts of IL-6–treated HepG2 cells showed an induced binding of SRE binding protein (SREBP)-1a and SRE binding protein(SREBP)-2 to the SRE-1 that was independent of the cellular sterol content and an induced binding of Sp1 and Sp3 to repeat 3 of the LDL-R promoter. Our data indicate that IL-6 induces stimulation of the LDL-R gene, resulting in enhanced gene transcription and LDL-R activity. This effect is sterol independent and involves, on the molecular level, activation of nuclear factors binding to SRE-1 and the Sp1 binding site in repeat 2 and repeat 3 of the LDL-R promoter, respectively.