title: Interleukin-6 stimulates LDL receptor gene expression via activation of sterol-responsive and Sp1 binding elements.
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 (125)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.
authors.affiliation: Department of Clinical Chemistry, University Hospital Freiburg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Gierens
authors.forename: M
authors.initials: M
authors.lastname: Nauck
authors.forename: M
authors.initials: M
authors.lastname: Roth
authors.forename: R
authors.initials: R
authors.lastname: Schinker
authors.forename: C
authors.initials: C
authors.lastname: Schürmann
authors.forename: H
authors.initials: H
authors.lastname: Scharnagl
authors.forename: G
authors.initials: G
authors.lastname: Neuhaus
authors.forename: H
authors.initials: H
authors.lastname: Wieland
authors.forename: W
authors.initials: W
authors.lastname: März
mesh_terms: D015152:Blotting, Northern; D022762:CCAAT-Enhancer-Binding Proteins; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006937:Hypercholesterolemia / Q000378:metabolism; D015850:Interleukin-6 / Q000494:pharmacology*; D007457:Iodine Radioisotopes; D008099:Liver / Q000166:cytology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010761:Phosphorus Radioisotopes; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D051705:Sp3 Transcription Factor; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D014162:Transfection
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D007457:Iodine Radioisotopes; D009687:Nuclear Proteins; D010761:Phosphorus Radioisotopes; D012333:RNA, Messenger; D011973:Receptors, LDL; C497121:SP3 protein, human; C497387:SREBF1 protein, human; C497390:SREBF2 protein, human; D016329:Sp1 Transcription Factor; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; D051705:Sp3 Transcription Factor