title: Inflammatory signaling and aryl hydrocarbon receptor mediate synergistic induction of interleukin 6 in MCF-7 cells.
abstract: The pleiotropic cytokine interleukin 6 (IL-6) is involved in immune cell homeostasis. Additionally, IL-6 expression and signaling in tumor cells have been shown to elicit both protumor and antitumor properties. There is a plethora of mechanistic knowledge regarding how IL-6 signal transduction translates to biological responses. However, there is little understanding as to what factors control IL-6 expression within a tumor cell environment. The studies presented herein show that, in MCF-7 breast and ECC-1 endocervical cancer cells, the stimulation of aryl hydrocarbon receptor (AHR) activity, in combination with IL-1beta or phorbol 12-myristate 13-acetate (PMA) treatment, results in a marked synergistic induction of IL-6 levels over what is seen without AHR activation. Chromatin immunoprecipitation experiments suggest that the regulation of IL-6 mRNA expression occurs at the chromatin level, as AHR presence on the IL-6 promoter was observed in response to treatment with AHR ligand. Synergistic induction of IL-6 expression was sustained for 72 hours, with accumulation of IL-6 protein reaching levels 4.8-fold above IL-1beta treatment alone. In addition, transcriptional regulation of the prototypic AHR responsive gene Cyp1a1 was negatively regulated by PMA and IL-1beta treatment. Silencing of RELA expression alleviated IL-1beta-mediated repression of AHR transcriptional activity, whereas PMA-mediated repression was maintained. Additionally, small interfering RNA studies reveal that AHR and RELA are necessary for synergistic induction of IL-6. The findings presented here reveal the AHR as a potential therapeutic target for selective modulation of IL-6 expression in some tumor cell types. The data also suggest a possible previously unrecognized mechanism of AHR-mediated tumor promotion.
authors.affiliation: Department of Veterinary and Biomedical Sciences and Center for Molecular Toxicology and Carcinogenesis, Pennsylvania State University, University Park, Pennsylvania, USA.
authors.forename: Brett D
authors.initials: BD
authors.lastname: Hollingshead
authors.forename: Timothy V
authors.initials: TV
authors.lastname: Beischlag
authors.forename: Brett C
authors.initials: BC
authors.lastname: Dinatale
authors.forename: Preeti
authors.initials: P
authors.lastname: Ramadoss
authors.forename: Gary H
authors.initials: GH
authors.lastname: Perdew
mesh_terms: D002454:Cell Differentiation; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007249:Inflammation; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D008024:Ligands; D008954:Models, Biological; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D008024:Ligands; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D012313:RNA