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 - 06/10/15
, Jacqueline Yvonne Cephus, BA a, Madison G. Boswell, BS a, John M. Fahrenholz, MD a, Emily W. Langley, MD a, Amy S. Feldman, MD a, Weisong Zhou, PhD a, Daniel E. Dulek, MD b, Kasia Goleniewska, MS a, Kimberly B. Woodward, RN, BSN a, Carla M. Sevin, MD a, Robert G. Hamilton, PhD c, Jay K. Kolls, MD d, R. Stokes Peebles, MD aAbstract |
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.
Le texte complet de cet article est disponible en PDF.Key words : Estrogen, IL-17A, IL-23 signaling, Let-7f, progesterone, severe asthma
Abbreviations used : AhR, BAL, E2, FITC, GAPDH, ILC3, IL-23R, IRF-4, miRNA, OVA, P4, PE, qPCR, ROR, SLE, STAT, WT
Plan
| Supported by the National Institutes of Health (U19 AI 095227, R01 AI 111820, R01 HL122554, and K12HD043483-08), the Department of Veterans Affairs (2I01BX000624), and the Vanderbilt Institute for Clinical and Translational Research (VICTR; grant VR576). |
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| Disclosure of potential conflict of interest: D. C. Newcomb has received research support from the National Institutes of Health (NIH), has received travel support from the Collegium of Internationale Allergologicum, and has received payment for lectures from the American Thoracic Society. J. Y. Cephus, W. Zhou, and K. B. Woodward have received research support from the NIH. M. G. Boswell has received research support from Vanderbilt University. D. E. Dulek has received research support and payment for lectures from the NIH. K. Goleniewska and R. S. Peebles have received research support from the NIH and the Department of Veterans' Affairs. J. K. Kolls has received research support from the NIH, has consultant arrangements with Boehringer Ingelheim, and has received stock/stock options from MiniVax. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 136 - N° 4
P. 1025 - octobre 2015 Retour au numéro
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