Estrogen and progesterone decrease let-7f microRNA expression and increase IL-23/IL- 23 receptor signaling and IL-17A production in patients with severe.

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Presentation transcript:

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, PhD, Jacqueline Yvonne Cephus, BA, Madison G. Boswell, BS, John M. Fahrenholz, MD, Emily W. Langley, MD, Amy S. Feldman, MD, Weisong Zhou, PhD, Daniel E. Dulek, MD, Kasia Goleniewska, MS, Kimberly B. Woodward, RN, BSN, Carla M. Sevin, MD, Robert G. Hamilton, PhD, Jay K. Kolls, MD, R. Stokes Peebles, MD Journal of Allergy and Clinical Immunology Volume 136, Issue 4, Pages 1025-1034.e11 (October 2015) DOI: 10.1016/j.jaci.2015.05.046 Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 IL-17A+ memory TH17 cell numbers are increased in women compared with men with severe asthma. A-C, Percentages and total numbers of IL-17A–producing CCR6+ memory TH17 cells in healthy control subjects and patients with severe asthma. *P < .05, Mann-Whitney U test; n = 9 healthy subjects and n = 29 patients with severe asthma patients (combined women and men). D and E, Percentages and total numbers of IL-17A+ memory TH17 cells in women and men with severe asthma. *P < .05, Mann-Whitney U test; n = 14 women and n = 15 men. Journal of Allergy and Clinical Immunology 2015 136, 1025-1034.e11DOI: (10.1016/j.jaci.2015.05.046) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 IL-17A protein expression is increased in TH0 and TH17 cells from women compared with those from men. A and B, Naive CD4+ T cells were differentiated into TH0 and TH17 cells. IL-17A and IL-17F protein expression was determined in TH0 and TH17 cells from healthy women (n = 13) or men (n = 14). *P < .05, Kruskal-Wallis test with Dunn posttest analysis. C, Total number of CD3+CD4+ TH17 cells. D-F, Percentages, total numbers, and/or geometric mean fluorescence intensity for CD3-gated CD4+IL-17A+ TH17 cells. *P < .05, Kruskal-Wallis test; n = 10 women and n = 12 men. n.s., Not significant. Journal of Allergy and Clinical Immunology 2015 136, 1025-1034.e11DOI: (10.1016/j.jaci.2015.05.046) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 IL-23R surface expression is increased and let-7f expression is decreased in TH17 cells from women compared with values in men. A and B, Dot plot and total IL-23R+CD3+CD4+ T cells from women and men. *P < .05, Kruskal-Wallis test with Dunn posttest analysis; n = 8 women and n = 7 men. C, Let-7f miRNA expression normalized to U6B expression in TH0 and TH17 cells from women and men. *P < .05, Kruskal-Wallis test with Dunn posttest analysis; n = 12 women and men. Journal of Allergy and Clinical Immunology 2015 136, 1025-1034.e11DOI: (10.1016/j.jaci.2015.05.046) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Let-7f decreased IL-23R surface expression and IL-17A production from TH17 cells. A 10 nmol/L let-7f inhibitor or negative control was transfected into naive T cells that were then differentiated into TH17 cells. A and B, Dot plots and total numbers of IL-17A+ TH17 cells. C, IL23R mRNA expression normalized to GAPDH. Dashes are means. *P < .05, Wilcoxon matched pairs test; n = 9 women and n = 9 men. Journal of Allergy and Clinical Immunology 2015 136, 1025-1034.e11DOI: (10.1016/j.jaci.2015.05.046) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 IL-17A protein expression is increased in TH0 and TH17 cells from female mice compared with that in TH0 and TH17 cells from male mice. A-C, IL-17A and IL-17F protein expression or il23r mRNA expression normalized to gapdh in TH0 and TH17 cells from female and male adult or prepubescent mice. D, IL-17A protein expression from adult TH17 cells differentiated with rmIL-23 (0-30 ng/mL). *P < 0.05, ANOVA with Tukey posttest analysis; n = 6, 2 experiments. Journal of Allergy and Clinical Immunology 2015 136, 1025-1034.e11DOI: (10.1016/j.jaci.2015.05.046) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 In vivo administration of 17β-E2 and P4 increased IL-17A protein expression and il23r mRNA expression from in vitro TH17 cells. Hormones or vehicle pellets (Veh.) were implanted into mice for 21 days, followed by naive T-cell isolation and TH17 cell differentiation. A, IL-17A protein expression. B, il23r mRNA expression normalized to gapdh. C, Let-7f miRNA expression normalized to u6b expression. *P < .05, Kruskal-Wallis test with Dunn posttest analysis; n = TH17 cells from 5 to 10 mice for each group, 2 experiments. Journal of Allergy and Clinical Immunology 2015 136, 1025-1034.e11DOI: (10.1016/j.jaci.2015.05.046) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 Adoptive transfer of TH17 cells from female D011.10 mice increases neutrophilic infiltration in the airways of WT female recipient mice. A, Schematic of experimental protocol. B-D, Total number of OVA-specific CD3+CD4+ T cells (Fig 7, B) or percentage and total number of IL-17A+ OVA-specific CD3+CD4+ TH17 cells (Fig 7, C and D) in lungs of recipient mice on day 4. E, CXCL1 (KC) protein expression in whole-lung homogenates. F, Total neutrophils in BAL fluid. *P < .05, ANOVA with Tukey posttest analysis; n = 10 to 12 recipient mice per group administered D011.10 TH17 cells from female or male mice combined from 2 experiments. Journal of Allergy and Clinical Immunology 2015 136, 1025-1034.e11DOI: (10.1016/j.jaci.2015.05.046) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 IL-4+ memory T-cell counts are similar in women and men with severe asthma. A-C, Percentages and total numbers of IL-17A/IL-4+ memory TH17 cells in women and men with severe asthma. D and E, Percentages and total numbers for IL-4+CD3+CD4+ memory T cells in women and men with severe asthma. n = 14 women and n = 15 men. F, Spearman correlation of total IgE plasma levels and IL-17A–producing CCR6+ memory TH17 cells. n.s., Not significant. Journal of Allergy and Clinical Immunology 2015 136, 1025-1034.e11DOI: (10.1016/j.jaci.2015.05.046) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Cytokine expression in human TH17-differentiated cells from women and men. A-C, Naive T cells isolated from healthy women (circles) and men (squares) were differentiated into TH17 cells. Cell-culture supernatants were harvested and analyzed for protein expression. *P < .05, Mann-Whitney U test; n = 13 TH17 cells from women and n = 14 TH17 cells from men. Journal of Allergy and Clinical Immunology 2015 136, 1025-1034.e11DOI: (10.1016/j.jaci.2015.05.046) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 IL-17A protein expression in TH17 cells from women does not correlate with 17β-E2 and P4 plasma levels. A and B, Spearman nonparametric correlations of 17β-E2 or P4 plasma concentrations and IL-17A protein expression from TH17 cell-culture supernatants; r and P values are listed on the graphs. C, Naive T cells isolated from healthy women and men were differentiated into TH17 cells in the presence of 17β-E2 or vehicle (ethanol). Four days after differentiation, IL-17A protein expression was determined from cell-culture supernatants. Data are representative of 8 TH17 cells from women and 5 TH17 cells from men. *P < .05, ANOVA with Tukey posttest analysis. Journal of Allergy and Clinical Immunology 2015 136, 1025-1034.e11DOI: (10.1016/j.jaci.2015.05.046) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 IL-23R surface expression is increased in memory TH17 cells from women with severe asthma compared with that in men with severe asthma. IL-23R surface expression was determined on CD3+CD4+CCR6+ memory TH17 cells from women and men with severe asthma. *P < .05, Mann-Whitney U test; n = 8 women and n = 7 men. Journal of Allergy and Clinical Immunology 2015 136, 1025-1034.e11DOI: (10.1016/j.jaci.2015.05.046) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Let-7f miRNA expression is decreased in TH17 cells transfected with let-7f inhibitor. Let-7f inhibitor (10 nmol/L) or negative control (10 nmol/L) were transfected into naive T cells isolated from healthy women and men. Cells were differentiated into TH17 cells, and Let-7f miRNA expression was determined by using qPCR and normalized to U6B expression. *P < .05, Wilcoxon matched paired test; n = 9 TH17 cells from women and n = 9 TH17 cells from men. Journal of Allergy and Clinical Immunology 2015 136, 1025-1034.e11DOI: (10.1016/j.jaci.2015.05.046) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 IL-13 and IFN-γ protein expression in TH17 cells. Hormones or vehicle pellets (Veh.) were implanted into mice for 21 days. Naive T cells were isolated from the spleens of mice, and TH17 cells were differentiated. As positive controls, TH1 and TH2 cells were differentiated from sham-operated female mice administered vehicle pellets. IFN-γ and IL-13 protein expression was determined by using ELISA. *P < .05 compared with TH17 cells from sham-operated female mice administered vehicle pellets, Kruskal-Wallis test with Dunn posttest analysis; n = 5 to 10 mice per group combined from 2 experiments. Journal of Allergy and Clinical Immunology 2015 136, 1025-1034.e11DOI: (10.1016/j.jaci.2015.05.046) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E7 Role of 17β-E2 and P4 in IL-17A protein expression from TH17 cells. The schematic proposes how increased 17β-E2 and P4 concentrations in women affect IL-17A protein expression from TH17 cells. Journal of Allergy and Clinical Immunology 2015 136, 1025-1034.e11DOI: (10.1016/j.jaci.2015.05.046) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions