The injectable-only contraceptive medroxyprogesterone acetate, unlike norethisterone acetate and progesterone, regulates inflammatory genes in endocervical cells via the glucocorticoid receptor.
The injectable-only contraceptive medroxyprogesterone acetate, unlike norethisterone acetate and progesterone, regulates inflammatory genes in endocervical cells via the glucocorticoid receptor.
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DOI：
10.1371/journal.pone.0096497
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Hapgood JP
中科院分区：
文献类型：
--
作者：
Govender Y;Avenant C;Verhoog NJ;Ray RM;Grantham NJ;Africander D;Hapgood JP
临床研究表明，与注射避孕药庚酸炔诺酮 (NET-EN) 不同，注射避孕药醋酸甲羟孕酮 (MPA) 会增加对 HIV-1 等感染的易感性。我们在 End1/E6E7 细胞系模型中研究了 MPA 与 NET 和孕酮 (P4) 相比，MPA 对宫颈内膜上皮（女性生殖器粘膜病原体进入的关键点）的差异效应、分子作用机制以及类固醇受体参与基因表达的影响。与 NET-醋酸盐 (NET-A) 和 P4 不同，MPA 会增加抗炎 GILZ 和 IκBα 基因的 mRNA 表达。同样，与 NET-A 不同，MPA 会降低促炎性 IL-6、IL-8 和 RANTES 基因的 mRNA 表达，以及 IL-6 和 IL-8 蛋白水平。 End1/E6E7 和原代宫颈内上皮细胞中表达的主要类固醇受体是糖皮质激素受体 (GR)，GR 敲低实验表明 MPA 的抗炎作用是由 GR 介导的。染色质免疫沉淀结果表明，与 NET-A 和 P4 不同，MPA 通过将 GR 招募到细胞因子基因启动子（如 GR 激动剂地塞米松）的机制来抑制宫颈上皮细胞中促炎细胞因子基因的表达。这至少部分与对转录的直接影响一致，不需要新的蛋白质合成。剂量反应分析表明，MPA 具有约 24 nM 的抗炎 GILZ 基因反式激活效力和约 4-20 nM 的促炎基因抑制效力，表明这些作用可能与注射避孕剂量的 MPA 相关。这些发现表明，在生殖器粘膜的背景下，鉴于 GR 在原代宫颈内膜上皮细胞中的主要表达，MPA 在宫颈上皮细胞中的这些 GR 介导的糖皮质激素样作用可能在区分不同孕激素和 P4 引起的炎症的影响以及因此对生殖器感染的易感性方面发挥关键作用。
Clinical studies suggest that the injectable contraceptive medroxyprogesterone acetate (MPA) increases susceptibility to infections such as HIV-1, unlike the injectable contraceptive norethisterone enanthate (NET-EN). We investigated the differential effects, molecular mechanism of action and steroid receptor involvement in gene expression by MPA as compared to NET and progesterone (P4) in the End1/E6E7 cell line model for the endocervical epithelium, a key point of entry for pathogens in the female genital mucosa. MPA, unlike NET-acetate (NET-A) and P4, increases mRNA expression of the anti-inflammatory GILZ and IκBα genes. Similarly, MPA unlike NET-A, decreases mRNA expression of the pro-inflammatory IL-6, IL-8 and RANTES genes, and IL-6 and IL-8 protein levels. The predominant steroid receptor expressed in the End1/E6E7 and primary endocervical epithelial cells is the glucocorticoid receptor (GR), and GR knockdown experiments show that the anti-inflammatory effects of MPA are mediated by the GR. Chromatin-immunoprecipitation results suggest that MPA, unlike NET-A and P4, represses pro-inflammatory cytokine gene expression in cervical epithelial cells via a mechanism involving recruitment of the GR to cytokine gene promoters, like the GR agonist dexamethasone. This is at least in part consistent with direct effects on transcription, without a requirement for new protein synthesis. Dose response analysis shows that MPA has a potency of ∼24 nM for transactivation of the anti-inflammatory GILZ gene and ∼4–20 nM for repression of the pro-inflammatory genes, suggesting that these effects are likely to be relevant at injectable contraceptive doses of MPA. These findings suggest that in the context of the genital mucosa, these GR-mediated glucocorticoid-like effects of MPA in cervical epithelial cells are likely to play a critical role in discriminating between the effects on inflammation caused by different progestins and P4 and hence susceptibility to genital infections, given the predominant expression of the GR in primary endocervical epithelial cells.
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DOI：
10.1016/0022-4731(83)90017-1
发表时间：
1983-01-01
影响因子：
4.1
作者：
FOTHERBY, K
通讯作者：
FOTHERBY, K
影响因子：
3.1
作者：
Fichorova, RN;Desai, PJ;Genco, CA
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Genco, CA
DOI：
10.1016/0022-4731(89)90098-8
发表时间：
1989-01-01
影响因子：
4.1
作者：
BRINKMANN, AO;FABER, PW;TRAPMAN, J
通讯作者：
TRAPMAN, J
影响因子：
56.9
作者：
AUPHAN, N;DIDONATO, JA;KARIN, M
通讯作者：
KARIN, M
DOI：
10.1016/j.bbrc.2013.02.086
发表时间：
2013-04-12
影响因子：
3.1
作者：
Africander, Donita;Louw, Renate;Hapgood, Janet P.
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Hapgood, Janet P.