Vaginal progesterone, but not 17α-hydroxyprogesterone caproate, has antiinflammatory effects at the murine maternal-fetal interface.
Vaginal progesterone, but not 17α-hydroxyprogesterone caproate, has antiinflammatory effects at the murine maternal-fetal interface.
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DOI：
10.1016/j.ajog.2015.08.010
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发表时间：
2015-12
影响因子：
9.8
通讯作者：
Gomez-Lopez N
中科院分区：
文献类型：
--
作者：
Furcron AE;Romero R;Plazyo O;Unkel R;Xu Y;Hassan SS;Chaemsaithong P;Mahajan A;Gomez-Lopez N
孕激素(阴道孕酮或17-羟基孕酮己酸酯[17OHP-C])应用于有早产风险的患者被广泛用于预防早产。这些药物预防肺结核的机制还知之甚少。孕激素具有免疫调节功能，因此，我们研究了阴道孕酮和17OHP-C对分娩过程中涉及的适应性和先天免疫细胞的局部影响。妊娠C57BL/6J小鼠于妊娠第13~17天经阴道孕酮(每200μL 1 mg，n=10)或黄体酮(对照组，200μL，n=10)或于第13、15、17天皮下注射17OHP-C(每100μL 2 mg，n=10)或蓖麻油(对照，100μL，n=10)。在足月分娩前(18.5DPC)分离蜕膜和子宫肌层白细胞，用流式细胞仪进行免疫表型鉴定。采集宫颈组织，用原位酶谱法检测基质金属蛋白酶-9活性，用Masson‘s三色染色观察胶原含量。用双抗体夹心法测定孕酮、雌二醇和细胞因子(干扰素-γ、白介素1β、IL-2、IL-4、IL-5、IL-6、IL-10、IL-12p70、KC/GRO和肿瘤坏死因子-α)的浓度。孕鼠经阴道孕酮或Replens处理后，在16.5dpc注射10μg内毒素(n=10)，并通过红外线摄像机监测至分娩，以确定阴道孕酮对肺结核发生率的影响。结果发现：(1)阴道孕酮增加蜕膜CD_4~+T细胞的比例，而不是17OHP-C；(2)阴道孕酮降低蜕膜CD_8~+CD_(25)+Foxp~+T细胞和巨噬细胞的比例；(3)阴道孕酮不引起M1-→M_2巨噬细胞极化，但降低子宫肌层干扰素γ~+中性粒细胞和单核细胞的比例；(5)阴道孕酮免疫效应与全身IL-1β浓度的降低有关，但与孕酮或雌二醇浓度的变化无关；(6)阴道孕酮预处理对内毒素诱导的肺结核有保护作用(效应值为50%，P=0.008)。阴道孕酮，而不是17OHP-C，在母胎界面和宫颈具有局部抗炎作用，并对内毒素诱导的肺结核具有保护作用。
Progestogen (vaginal progesterone or 17-alpha-hydroxyprogesterone caproate [17OHP-C]) administration to patients at risk for preterm delivery is widely used for the prevention of preterm birth (PTB). The mechanisms by which these agents prevent PTB are poorly understood. Progestogens have immunomodulatory functions; therefore, we investigated the local effects of vaginal progesterone and 17OHP-C on adaptive and innate immune cells implicated in the process of parturition. Pregnant C57BL/6J mice received vaginal progesterone (1 mg per 200 μL, n = 10) or Replens (control, 200 μL, n = 10) from 13 to 17 days postcoitum (dpc) or were subcutaneously injected with 17OHP-C (2 mg per 100 μL, n = 10) or castor oil (control, 100 μL, n = 10) on 13, 15, and 17 dpc. Decidual and myometrial leukocytes were isolated prior to term delivery (18.5 dpc) for immunophenotyping by flow cytometry. Cervical tissues were collected to determine matrix metalloproteinase (MMP)-9 activity by in situ zymography and visualization of collagen content by Masson’s trichrome staining. Plasma concentrations of progesterone, estradiol, and cytokines (interferon [IFN]-γ, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, KC/GRO, and tumor necrosis factor-α) were quantified by enzyme-linked immunosorbent assays. Pregnant mice pretreated with vaginal progesterone or Replens were injected with 10 μg of an endotoxin on 16.5 dpc (n = 10 each) and monitored via infrared camera until delivery to determine the effect of vaginal progesterone on the rate of PTB. The following results were found: (1) vaginal progesterone, but not 17OHP-C, increased the proportion of decidual CD4+ T-regulatory cells; (2) vaginal progesterone, but not 17OHP-C, decreased the proportion of decidual CD8+CD25+Foxp3+ T cells and macrophages; (3) vaginal progesterone did not cause an M1→M2 macrophage polarization but reduced the proportion of myometrial IFNγ+ neutrophils and cervical active MMP-9-positive neutrophils and monocytes; (4) 17OHP-C did not reduce the proportion of myometrial IFNy-positive neutrophils; however, it increased the abundance of cervical active MMP-9-positive neutrophils and monocytes; (5) vaginal progesterone immune effects were associated with reduced systemic concentrations of IL-1β but not with alterations in progesterone or estradiol concentrations; and (6) vaginal progesterone pretreatment protected against endotoxin-induced PTB (effect size 50%, P = .008). Vaginal progesterone, but not 17OHP-C, has local antiinflammatory effects at the maternal-fetal interface and the cervix and protects against endotoxin-induced PTB.