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

Dawn C. Newcomb; Jacqueline Yvonne Cephus; Madison G. Boswell; John M. Fahrenholz; Emily W. Langley; Amy S. Feldman; Weisong Zhou; Daniel E. Dulek; Kasia Goleniewska; Kimberly B. Woodward; Carla M. Sevin; Robert G. Hamilton; Jay K. Kolls; R. Stokes Peebles

doi:10.1016/j.jaci.2015.05.046

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

Dawn C. Newcomb, Jacqueline Yvonne Cephus, Madison G. Boswell, John M. Fahrenholz, Emily W. Langley, Amy S. Feldman, Weisong Zhou, Daniel E. Dulek, Kasia Goleniewska, Kimberly B. Woodward, Carla M. Sevin, Robert G. Hamilton, Jay K. Kolls, R. Stokes Peebles

School of Medicine

Research output: Contribution to journal › Article › peer-review

54 Scopus citations

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 T_H17 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 T_H17-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 T_H17 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 T_H17 cells from female and male mice. Results In patients with severe asthma and healthy control subjects, IL-17A production was increased in T_H17 cells from women compared with men. IL-23R expression was increased and let-7f expression was decreased in T_H17-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 T_H17 cells from mice administered 17β-E2+P4 compared with those administered vehicle. Furthermore, transfer of female OVA-specific T_H17 cells increased acute neutrophil infiltration in the lungs of OVA-challenged recipient mice compared with transfer of male OVA-specific T_H17 cells. Conclusions 17β-E2+P4 increased IL-17A production from T_H17 cells, providing a potential mechanism for the increased prevalence of severe asthma in women compared with men.

Original language	English (US)
Pages (from-to)	1025-1034.e11
Journal	Journal of Allergy and Clinical Immunology
Volume	136
Issue number	4
DOIs	https://doi.org/10.1016/j.jaci.2015.05.046
State	Published - Oct 2015

Keywords

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

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1016/j.jaci.2015.05.046

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Newcomb, D. C., Cephus, J. Y., Boswell, M. G., Fahrenholz, J. M., Langley, E. W., Feldman, A. S., Zhou, W., Dulek, D. E., Goleniewska, K., Woodward, K. B., Sevin, C. M., Hamilton, R. G., Kolls, J. K., & Peebles, R. S. (2015). 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. Journal of Allergy and Clinical Immunology, 136(4), 1025-1034.e11. https://doi.org/10.1016/j.jaci.2015.05.046

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. / Newcomb, Dawn C.; Cephus, Jacqueline Yvonne; Boswell, Madison G. et al.
In: Journal of Allergy and Clinical Immunology, Vol. 136, No. 4, 10.2015, p. 1025-1034.e11.

Research output: Contribution to journal › Article › peer-review

Newcomb, DC, Cephus, JY, Boswell, MG, Fahrenholz, JM, Langley, EW, Feldman, AS, Zhou, W, Dulek, DE, Goleniewska, K, Woodward, KB, Sevin, CM, Hamilton, RG, Kolls, JK & Peebles, RS 2015, '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', Journal of Allergy and Clinical Immunology, vol. 136, no. 4, pp. 1025-1034.e11. https://doi.org/10.1016/j.jaci.2015.05.046

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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.",

keywords = "Estrogen, IL-17A, IL-23 signaling, Let-7f, progesterone, severe asthma",

author = "Newcomb, {Dawn C.} and Cephus, {Jacqueline Yvonne} and Boswell, {Madison G.} and Fahrenholz, {John M.} and Langley, {Emily W.} and Feldman, {Amy S.} and Weisong Zhou and Dulek, {Daniel E.} and Kasia Goleniewska and Woodward, {Kimberly B.} and Sevin, {Carla M.} and Hamilton, {Robert G.} and Kolls, {Jay K.} and Peebles, {R. Stokes}",

note = "Publisher Copyright: {\textcopyright} 2015 American Academy of Allergy, Asthma & Immunology.",

year = "2015",

month = oct,

doi = "10.1016/j.jaci.2015.05.046",

language = "English (US)",

volume = "136",

pages = "1025--1034.e11",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Mosby Inc.",

number = "4",

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TY - JOUR

T1 - 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

AU - Newcomb, Dawn C.

AU - Cephus, Jacqueline Yvonne

AU - Boswell, Madison G.

AU - Fahrenholz, John M.

AU - Langley, Emily W.

AU - Feldman, Amy S.

AU - Zhou, Weisong

AU - Dulek, Daniel E.

AU - Goleniewska, Kasia

AU - Woodward, Kimberly B.

AU - Sevin, Carla M.

AU - Hamilton, Robert G.

AU - Kolls, Jay K.

AU - Peebles, R. Stokes

PY - 2015/10

Y1 - 2015/10

N2 - 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.

AB - 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.

KW - Estrogen

KW - IL-17A

KW - IL-23 signaling

KW - Let-7f

KW - progesterone

KW - severe asthma

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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

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