The interleukin-6-type cytokine oncostatin M induces arylhydrocarbon receptor expression in a STAT3-dependentmanner in human HepG2 hepatoma cells

摘要

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcriptionfactor that mediates the toxicity of dioxins, polycyclic aromatic hydrocarbonsand related environmental pollutants. Besides drug metabolism, severalstudies have provided evidence that the AHR and its downstreamtargets trigger important developmental, physiological and pathophysiologicalprocesses. However, in contrast to the molecular mechanisms of AHRdependentsignaling pathways, the transcriptional regulation of the AHRgene itself is as yet only marginally understood. We found that the pleiotropicinterleukin (IL)-6-type cytokine oncostatin M (OSM) is an inducerof AHR mRNA and protein expression in human HepG2 hepatocarcinomacells. Analyses of the human AHR promoter revealed the existence of aputative signal transducer and activator of transcription (STAT)-bindingelement 5′-upstream of the transcription start site. By means of site-directedmutagenesis, inhibitor experiments and electrophoretic mobility shiftassays, we demonstrated that this STAT motif is recognized by STAT3 toregulate basal and cytokine-inducible AHR expression in HepG2 cells. Theidentification of the AHR as a downstream target of IL-6-type cytokinestimulatedSTAT3 signaling may contribute to a better understanding ofthe multiple facets of AHR during development, physiology and disease.