title: Estrogen and progesterone decrease let-7f microRNA expression and increase IL-23/IL-23 receptor signaling and IL-17A production in patients with severe asthma.
abstract: BACKGROUND
  Women have an increased prevalence of severe asthma compared with men. IL-17A is associated with severe asthma and requires IL-23 receptor (IL-23R) signaling, which is negatively regulated by let-7f microRNA.
  
  
  OBJECTIVE
  We sought to Determine the mechanism by which 17β-estradiol (E2) and progesterone (P4) increase IL-17A production.
  
  
  METHODS
  IL-17A production was determined by using flow cytometry in TH17 cells from women (n = 14) and men (n = 15) with severe asthma. Cytokine levels were measured by using ELISA, and IL-23R and let-7f expression was measured by using quantitative PCR in TH17-differentiated cells from healthy women (n = 13) and men (n = 14). In sham-operated or ovariectomized female mice, 17β-E2, P4, 17β-E2+P4, or vehicle pellets were administered for 3 weeks before ex vivo TH17 cell differentiation. Airway neutrophil infiltration and CXCL1 (KC) expression were also determined in ovalbumin (OVA)-challenged wild-type female recipient mice with an adoptive transfer of OVA-specific TH17 cells from female and male mice.
  
  
  RESULTS
  In patients with severe asthma and healthy control subjects, IL-17A production was increased in TH17 cells from women compared with men. IL-23R expression was increased and let-7f expression was decreased in TH17-differentiated cells from women compared with men. In ovariectomized mice IL-17A and IL-23R expression was increased and Let-7f expression was decreased in TH17 cells from mice administered 17β-E2+P4 compared with those administered vehicle. Furthermore, transfer of female OVA-specific TH17 cells increased acute neutrophil infiltration in the lungs of OVA-challenged recipient mice compared with transfer of male OVA-specific TH17 cells.
  
  
  CONCLUSIONS
  17β-E2+P4 increased IL-17A production from TH17 cells, providing a potential mechanism for the increased prevalence of severe asthma in women compared with men.
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn. Electronic address: dawn.newcomb@vanderbilt.edu.
authors.forename: Dawn C
authors.initials: DC
authors.lastname: Newcomb
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn.
authors.forename: Jacqueline Yvonne
authors.initials: JY
authors.lastname: Cephus
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn.
authors.forename: Madison G
authors.initials: MG
authors.lastname: Boswell
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn.
authors.forename: John M
authors.initials: JM
authors.lastname: Fahrenholz
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn.
authors.forename: Emily W
authors.initials: EW
authors.lastname: Langley
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Feldman
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn.
authors.forename: Weisong
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tenn.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Dulek
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn.
authors.forename: Kasia
authors.initials: K
authors.lastname: Goleniewska
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn.
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: Woodward
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn.
authors.forename: Carla M
authors.initials: CM
authors.lastname: Sevin
authors.affiliation: Department of Medicine and Pathology, Johns Hopkins University School of Medicine, Baltimore, Md.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Hamilton
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh, Philadelphia, Pa.
authors.forename: Jay K
authors.initials: JK
authors.lastname: Kolls
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn.
authors.forename: R Stokes
authors.initials: RS
authors.lastname: Peebles
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000473:pathology; D004967:Estrogens / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology*; D053759:Interleukin-23 / Q000276:immunology*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000276:immunology*; D008875:Middle Aged; D011374:Progesterone / Q000276:immunology*; D018123:Receptors, Interleukin / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology
chemical_list: D004967:Estrogens; C508717:IL17A protein, human; C515500:IL23R protein, human; C098680:Il17a protein, mouse; D020381:Interleukin-17; D053759:Interleukin-23; D035683:MicroRNAs; D018123:Receptors, Interleukin; C528688:interleukin-23 receptor, mouse; C487931:mirnlet7 microRNA, human; C542687:mirnlet7 microRNA, mouse; D011374:Progesterone
keywords: Estrogen; IL-17A; IL-23 signaling; Let-7f; progesterone; severe asthma