© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Interleukin-6 Stimulates LDL Receptor Gene Expression via Activation of Sterol-Responsive and Sp1 Binding Elements
From the Department of Clinical Chemistry (H.G., M.N., R.S., C.S., H.S., H.W., W.M.), University Hospital Freiburg, Freiburg, Germany; the Department of Research (M.R.), University Hospital Basel, Basel, Switzerland; and the Faculty of Biology (H.G., G.N.), Institute for Biology II/Cell Biology, Albert Ludwigs University Freiburg, Freiburg, Germany.
Correspondence to Dr Markus Nauck, University Hospital Freiburg, Department of Clinical Chemistry, Hugstetter Strasse 55, 79106 Freiburg, Germany. E-mail msnauck{at}med1.ukl.uni-freiburg.de
Abstract—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 125I-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.
Key Words: transcription factors • cholesterol • lipoproteins • receptors • hypocholesterolemia
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