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.
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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DOI：
10.1016/j.jaci.2015.05.046
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发表时间：
2015-10
期刊：
影响因子：
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通讯作者：
Peebles RS Jr
中科院分区：
文献类型：
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作者：
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 Jr
与男性相比，女性严重哮喘的患病率增加。IL-17 A与严重哮喘相关，需要IL-23受体（IL-23 R）信号转导，而IL-23 R信号转导受Let-7 f miRNA负调控。确定17β-雌二醇（E2）和孕酮（P4）增加IL-17 A产生的机制。通过流式细胞术测定患有严重哮喘的女性（n=14）和男性（n=15）的Th 17细胞中IL-17 A的产生。在来自健康女性（n=13）和男性（n=14）的Th 17分化细胞中，通过ELISA测量细胞因子水平，并通过qPCR测量IL-23 R和Let-7 f表达。在假手术或卵巢切除的雌性小鼠中，在离体Th 17细胞分化之前，给予17β-E2、P4、17β-E2+P4或载体颗粒3周。还在OVA攻击的WT雌性受体小鼠中测定了气道中性粒细胞浸润和KC表达，所述雌性受体小鼠具有来自雌性和雄性小鼠的OVA特异性Th 17细胞的过继转移。在严重哮喘患者和健康对照组中，与男性相比，女性Th 17细胞中IL-17 A的产生增加。与男性相比，女性Th 17分化细胞中IL-23 R表达增加，Let-7 f表达减少。在卵巢切除小鼠中，与溶媒相比，在来自给予17β-E2+P4的小鼠的Th 17细胞中，IL-17 A和IL-23 R表达增加，Let-7 f表达降低。此外，与转移雄性OVA特异性Th 17细胞相比，转移雌性OVA特异性Th 17细胞增加了OVA攻击的受体小鼠肺中的急性中性粒细胞浸润。17β-E2+P4增加了Th 17细胞产生IL-17 A的能力，为女性重度哮喘患病率高于男性提供了潜在机制。
Women have an increased prevalence of severe asthma compared to men. IL-17A is associated with severe asthma and requires IL-23 receptor (IL-23R) signaling, which is negatively regulated by Let-7f miRNA. Determine the mechanism by which 17β-estradiol (E2) and progesterone (P4) increase IL-17A production. IL-17A production was determined by flow cytometry in Th17 cells from women (n=14) and men (n=15) with severe asthma. Cytokine levels were measured by ELISA and IL-23R and Let-7f expression by qPCR 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 prior to ex vivo Th17 cell differentiation. Airway neutrophil infiltration and KC expression was also determined in OVA-challenged WT female recipient mice with an adoptive transfer of OVA-specific Th17 cells from female and male mice. In severe asthma patients and healthy controls, IL-17A production was increased in Th17 cells from women compared to men. IL-23R expression was increased and Let-7f expression was decreased in Th17 differentiated cells from women compared to men. In ovariectomized mice, IL-17A and IL-23R expression was increased and Let-7f expression was decreased in the Th17 cells from mice administered 17β-E2+P4 compared to vehicle. Further, transfer of female OVA-specific Th17 cells increased acute neutrophil infiltration in the lungs of OVA-challenged recipient mice compared to 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 to men.