title: Estrogen modulation of endosome-associated toll-like receptor 8: an IFNα-independent mechanism of sex-bias in systemic lupus erythematosus.
abstract: Females of child-bearing age are more resistant to infectious disease and have an increased risk of systemic lupus erythematosus (SLE). We hypothesized that estrogen-induced gene expression could establish an immunoactivated state which would render enhanced defense against infection, but may be deleterious in autoimmune development. Using peripheral blood mononuclear cells (PBMCs), we demonstrate enhanced responses with immunogen stimulation in the presence of 17β-estradiol (E2) and gene array analyses reveal toll-like receptor 8 (TLR8) as an E2-responsive candidate gene. TLR8 expression levels are up-regulated in SLE and PBMCs stimulated with TLR8 agonist display a female sex-biased, E2-sensitive response. Moreover, we identify a putative ERα-binding region near the TLR8 locus and blocking ERα expression significantly decreases E2-mediated TLR8 induction. Our findings characterize TLR8 as a novel estrogen target gene that can lower the inflammatory threshold and implicate an IFNα-independent inflammatory mechanism that could contribute to higher SLE incidence in women.
authors: Division of Rheumatology and Immunology, The Ohio State University, Columbus, OH 43210, USA; Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA; Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA.
authors: Nicholas A
authors: NA
authors: Young
authors: Division of Rheumatology and Immunology, The Ohio State University, Columbus, OH 43210, USA; Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA; Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA.
authors: Lai-Chu
authors: LC
authors: Wu
authors: Department of Molecular Genetics, The Ohio State University, Columbus, OH 43210, USA; Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA.
authors: Craig J
authors: CJ
authors: Burd
authors: Division of Rheumatology and Immunology, The Ohio State University, Columbus, OH 43210, USA; Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA; Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA.
authors: Alexandra K
authors: AK
authors: Friedman
authors: Division of Rheumatology and Immunology, The Ohio State University, Columbus, OH 43210, USA; Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA; Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA.
authors: Benjamin H
authors: BH
authors: Kaffenberger
authors: Center for Microbial Interface Biology, The Ohio State University, Columbus, OH 43210, USA; Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210, USA; Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA.
authors: Murugesan V S
authors: MV
authors: Rajaram
authors: Center for Microbial Interface Biology, The Ohio State University, Columbus, OH 43210, USA; Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210, USA; Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA.
authors: Larry S
authors: LS
authors: Schlesinger
authors: University of Virginia Health System, Medicine/Endocrinology, Charlottesville, VA 22908, USA.
authors: Hayley
authors: H
authors: James
authors: University of Virginia Health System, Medicine/Endocrinology, Charlottesville, VA 22908, USA.
authors: Margaret A
authors: MA
authors: Shupnik
authors: Division of Rheumatology and Immunology, The Ohio State University, Columbus, OH 43210, USA; Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA; Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA. Electronic address: Wael.Jarjour@osumc.edu.
authors: Wael N
authors: WN
authors: Jarjour
mesh_terms: D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D011992:Endosomes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007155:Immunologic Factors / Q000494:pharmacology; D016898:Interferon-alpha / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D012737:Sex Factors; D015398:Signal Transduction; D051200:Toll-Like Receptor 8 / Q000819:agonists / Q000235:genetics / Q000276:immunology*
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D007093:Imidazoles; D007155:Immunologic Factors; D016898:Interferon-alpha; C495349:TLR8 protein, human; D051200:Toll-Like Receptor 8; D004958:Estradiol; C402365:resiquimod
keywords: Autoimmunity; Estrogen; Sex-bias; Systemic lupus erythematosus; Toll-like receptor