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: Natalie Stobbe-Maicherski, Sandra Wolff, Christian Wolff, Josef Abel, Ulrich Sydlik, Katrin Frauenstein, Thomas Haarmann-Stemmann
• Journal: The FEBS journal (FEBS J) Vol. 280 Issue 24 Pg. 6681-90 (Dec 2013) ISSN: 1742-4658 [Electronic] England
• PMID: 24127753 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 FEBS.

Chemical References

• AHR protein, human
• Basic Helix-Loop-Helix Transcription Factors
• Interleukin-6
• RNA, Messenger
• Receptors, Aryl Hydrocarbon
• STAT3 Transcription Factor
• Oncostatin M
• Luciferases

Topics

• Basic Helix-Loop-Helix Transcription Factors (genetics, metabolism)
• Blotting, Western
• Chromatin Immunoprecipitation
• Electrophoretic Mobility Shift Assay
• Gene Expression Regulation, Neoplastic
• Hep G2 Cells
• Humans
• Interleukin-6 (metabolism)
• Luciferases (metabolism)
• Mutagenesis, Site-Directed
• Oncostatin M (genetics, metabolism)
• Promoter Regions, Genetic (genetics)
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Receptors, Aryl Hydrocarbon (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• STAT3 Transcription Factor (genetics, metabolism)