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      Estrogen modulation of endosome-associated toll-like receptor 8: an IFNα-independent mechanism of sex-bias in systemic lupus erythematosus.

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          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.

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          Author and article information

          Journal
          Clin. Immunol.
          Clinical immunology (Orlando, Fla.)
          1521-7035
          1521-6616
          Mar 2014
          : 151
          : 1
          Affiliations
          [1 ] 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.
          [2 ] Department of Molecular Genetics, The Ohio State University, Columbus, OH 43210, USA; Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA.
          [3 ] 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.
          [4 ] University of Virginia Health System, Medicine/Endocrinology, Charlottesville, VA 22908, USA.
          [5 ] 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.
          Article
          S1521-6616(14)00011-4 NIHMS569006
          10.1016/j.clim.2014.01.006
          24525049
          8fd666cc-67b7-4093-88c2-030e9c9b394a
          Copyright © 2014 Elsevier Inc. All rights reserved.
          History

          Autoimmunity,Estrogen,Sex-bias,Systemic lupus erythematosus,Toll-like receptor

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