title: The interleukin-6-type cytokine oncostatin M induces aryl hydrocarbon receptor expression in a STAT3-dependent manner in human HepG2 hepatoma cells.
abstract: The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that mediates the toxicity of dioxins, polycyclic aromatic hydrocarbons and related environmental pollutants. Besides drug metabolism, several studies have provided evidence that the AHR and its downstream targets trigger important developmental, physiological and pathophysiological processes. However, in contrast to the molecular mechanisms of AHR-dependent signaling pathways, the transcriptional regulation of the AHR gene itself is as yet only marginally understood. We found that the pleiotropic interleukin (IL)-6-type cytokine oncostatin M (OSM) is an inducer of AHR mRNA and protein expression in human HepG2 hepatocarcinoma cells. Analyses of the human AHR promoter revealed the existence of a putative signal transducer and activator of transcription (STAT)-binding element 5'-upstream of the transcription start site. By means of site-directed mutagenesis, inhibitor experiments and electrophoretic mobility shift assays, we demonstrated that this STAT motif is recognized by STAT3 to regulate basal and cytokine-inducible AHR expression in HepG2 cells. The identification of the AHR as a downstream target of IL-6-type cytokine-stimulated STAT3 signaling may contribute to a better understanding of the multiple facets of AHR during development, physiology and disease.
authors.affiliation: IUF - Leibniz Research Institute for Environmental Medicine, Duesseldorf, Germany.
authors.forename: Natalie
authors.initials: N
authors.lastname: Stobbe-Maicherski
authors.forename: Sandra
authors.initials: S
authors.lastname: Wolff
authors.forename: Christian
authors.initials: C
authors.lastname: Wolff
authors.forename: Josef
authors.initials: J
authors.lastname: Abel
authors.forename: Ulrich
authors.initials: U
authors.lastname: Sydlik
authors.forename: Katrin
authors.initials: K
authors.lastname: Frauenstein
authors.forename: Thomas
authors.initials: T
authors.lastname: Haarmann-Stemmann
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D053683:Oncostatin M / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015850:Interleukin-6; D008156:Luciferases; D053683:Oncostatin M; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D050796:STAT3 Transcription Factor; C111235:AHR protein, human
keywords: HepG2 cells; IL-6; STAT3; aryl hydrocarbon receptor; oncostatin M