title: Expression of murine Unc93b1 is up-regulated by interferon and estrogen signaling: implications for sex bias in the development of autoimmunity.
abstract: The endoplasmic reticulum transmembrane protein, Unc93b1, is essential for trafficking of endosomal TLRs from the endoplasmic reticulum to endosomes. A genetic defect in the human UNC93B1 gene is associated with immunodeficiency. However, systemic lupus erythematosus (SLE) patients express increased levels of the UNC93B1 protein in B cells. Because SLE in patients and certain mouse models exhibits a sex bias and increased serum levels of type I interferons in patients are associated with the disease activity, we investigated whether the female sex hormone estrogen (E2) or type I interferon signaling could up-regulate the expression of the murine Unc93b1 gene. We found that steady-state levels of Unc93b1 mRNA and protein were measurably higher in immune cells (CD3(+), B220(+), CD11b(+) and CD11c(+)) isolated from C57BL/6 (B6) females than age-matched males. Moreover, treatment of CD11b(+) and B220(+) cells with E2 or interferons (IFN-α, IFN-β or IFN-γ) significantly increased the levels of Unc93b1 mRNA and protein. Accordingly, a deficiency of estrogen receptor-α or STAT1 expression in immune cells decreased the expression levels of the Unc93b1 protein. Interestingly, levels of Unc93b1 protein were appreciably higher in B6.Nba2 lupus-prone female mice compared with age-matched B6 females. Furthermore, increased expression of the interferon- and E2-inducible p202 protein in a murine macrophage cell line (RAW264.7) increased the levels of the Unc93b1 protein, whereas knockdown of p202 expression reduced the levels. To our knowledge, our observations demonstrate for the first time that activation of interferon and estrogen signaling in immune cells up-regulates the expression of murine Unc93b1.
authors.affiliation: Department of Environmental Health, University of Cincinnati, 3223 Eden Avenue, PO Box 670056, Cincinnati, OH 45267, USA.
authors.forename: Ravichandran
authors.initials: R
authors.lastname: Panchanathan
authors.forename: Hongzhu
authors.initials: H
authors.lastname: Liu
authors.forename: Divaker
authors.initials: D
authors.lastname: Choubey
mesh_terms: D000818:Animals; D015551:Autoimmunity; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D007372:Interferons / Q000276:immunology*; D008297:Male; D026901:Membrane Transport Proteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D012727:Sex Characteristics; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D004967:Estrogens; D026901:Membrane Transport Proteins; C512254:UNC93B1 protein, mouse; D007372:Interferons
keywords: IFN; SLE; TLRs; Unc93b1; estrogen; innate immune response; p202