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

• Published in: Journal of allergy and clinical immunology Vol. 136; no. 4; pp. 1025 - 1034.e11
• Main Authors: Newcomb, Dawn C., Cephus, Jacqueline Yvonne, Boswell, Madison G., Fahrenholz, John M., Langley, Emily W., Feldman, Amy S., Zhou, Weisong, Dulek, Daniel E., Goleniewska, Kasia, Woodward, Kimberly B., Sevin, Carla M., Hamilton, Robert G., Kolls, Jay K., Peebles, R. Stokes
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2015; Elsevier Limited
• Subjects: Adolescent; Adult; Age; Allergy and Immunology; Animals; Asthma; Asthma - immunology; Asthma - pathology; Body mass index; Cytokines; Estrogen; Estrogens - immunology; Female; Gender differences; Gene Expression Regulation - immunology; Human subjects; Humans; IL-17A; IL-23 signaling; Inflammation; Interleukin-17 - immunology; Interleukin-23 - immunology; Laboratory animals; Let-7f; Lymphocytes; Male; Mice; MicroRNAs; MicroRNAs - immunology; Middle Aged; Ostomy; progesterone; Progesterone - immunology; Protein expression; Proteins; Receptors, Interleukin - immunology; Rodents; severe asthma; Signal Transduction - immunology; Th17 Cells - immunology; Th17 Cells - pathology; Womens health; IL-17A; P4; Estrogen; progesterone; AhR; BAL; E2; SLE; IRF-4; ILC3; FITC; IL-23R; STAT; Let-7f; ROR; PE; severe asthma; miRNA; qPCR; OVA; GAPDH; WT; IL-23 signaling; Fluorescein isothiocyanate; Signal transducer and activator of transcription; Estradiol; Systemic lupus erythematosus; Bronchoalveolar lavage; IL-23 receptor; Ovalbumin; Retionic acid–related orphan receptor; Quantitative PCR; Wild-type; Aryl hydrocarbon receptor; MicroRNA; Interferon regulatory factor 4; Phycoerythrin; Glyceraldehyde-3-phosphate dehydrogenase; Group 3 innate lymphoid cell
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2015.05.046

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. We sought to Determine the mechanism by which 17β-estradiol (E2) and progesterone (P4) increase IL-17A production. 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. 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. 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.