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J Allergy Clin Immunol. 2015 Oct;136(4):1025-34.e11. doi: 10.1016/j.jaci.2015.05.046. Epub 2015 Aug 1.

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.

Author information

1
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn. Electronic address: dawn.newcomb@vanderbilt.edu.
2
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn.
3
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tenn.
4
Department of Medicine and Pathology, Johns Hopkins University School of Medicine, Baltimore, Md.
5
Department of Pediatrics, Children's Hospital of Pittsburgh, Philadelphia, Pa.

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.

KEYWORDS:

Estrogen; IL-17A; IL-23 signaling; Let-7f; progesterone; severe asthma

PMID:
26242299
PMCID:
PMC4600442
DOI:
10.1016/j.jaci.2015.05.046
[Indexed for MEDLINE]
Free PMC Article

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