Bisphenol A (BPA) stimulates the interferon signaling and activates the inflammasome activity in myeloid cells.
Environmental factors contribute to the development of autoimmune diseases, including systemic lupus erythematosus (SLE), which exhibits a strong female bias (female-to-male ratio 9:1). However, the molecular mechanisms remain largely unknown. Because a feedforward loop between the female sex hormone estrogen (E2) and type I interferon (IFN-α/β)-signaling induces the expression of certain p200-family proteins (such as murine p202 and human IFI16) that regulate innate immune responses and modify lupus susceptibility, we investigated whether treatment of myeloid cells with bisphenol A (BPA), an environmental estrogen, could regulate the p200-family proteins and activate innate immune responses. We found that treatment of murine bone marrow-derived cells (BMCs) and human peripheral blood mononuclear cells with BPA induced the expression of ERα and IFN-β, activated the IFN-signaling, and stimulated the expression of the p202 and IFI16 proteins. Further, the treatment increased levels of the NLRP3 inflammasome and stimulated its activity. Accordingly, BPA-treatment of BMCs from non lupus-prone C57BL/6 and the lupus-prone (NZB×NZW)F1 mice activated the type I IFN-signaling, induced the expression of p202, and activated an inflammasome activity. Our study demonstrates that BPA-induced signaling in the murine and human myeloid cells stimulates the type I IFN-signaling that results in an induction of the p202 and IFI16 innate immune sensors for the cytosolic DNA and activates an inflammasome activity. These observations provide novel molecular insights into the role of environmental BPA exposures in potentiating the development of certain autoimmune diseases such as SLE.
Department of Environmental Health, University of Cincinnati, 3223 Eden Avenue, P. O. Box-670056, Cincinnati, OH 45267, USA; Cincinnati VA Medical Center, 3200 Vine Street, Cincinnati, OH 45220, USA.
Ravichandran
R
Panchanathan
Department of Environmental Health, University of Cincinnati, 3223 Eden Avenue, P. O. Box-670056, Cincinnati, OH 45267, USA; Cincinnati VA Medical Center, 3200 Vine Street, Cincinnati, OH 45220, USA.
Hongzhu
H
Liu
Department of Environmental Health, University of Cincinnati, 3223 Eden Avenue, P. O. Box-670056, Cincinnati, OH 45267, USA.
Yuet-Kin
YK
Leung
Department of Environmental Health, University of Cincinnati, 3223 Eden Avenue, P. O. Box-670056, Cincinnati, OH 45267, USA.
Shuk-mei
SM
Ho
Department of Environmental Health, University of Cincinnati, 3223 Eden Avenue, P. O. Box-670056, Cincinnati, OH 45267, USA; Cincinnati VA Medical Center, 3200 Vine Street, Cincinnati, OH 45220, USA. Electronic address: Divaker.choubey@uc.edu.
Divaker
D
Choubey
D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D002460:Cell Line; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D058847:Inflammasomes / Q000187:drug effects / Q000378:metabolism*; D007372:Interferons / Q000235:genetics*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics; D008297:Male; D051379:Mice; D022423:Myeloid Cells / Q000166:cytology / Q000187:drug effects*; D010636:Phenols / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D047628:Estrogen Receptor alpha; D058847:Inflammasomes; D007372:Interferons; D010636:Phenols; C006780:bisphenol A; D000098826:Bisphenol A Compounds
Bisphenol A; Estrogen; IFN-β; Inflammasome; Lupus susceptibility; p202