Pro-inflammatory signals induce 20α-HSD expression in myometrial cells: A key mechanism for local progesterone withdrawal.
Pro-inflammatory signals induce 20α-HSD expression in myometrial cells: A key mechanism for local progesterone withdrawal.
复制标题
DOI：
10.1111/jcmm.16681
复制
发表时间：
2021-07
影响因子：
5.3
通讯作者：
Lye SJ
中科院分区：
文献类型：
--
作者：
Nadeem L;Balendran R;Dorogin A;Mesiano S;Shynlova O;Lye SJ
子宫肌瘤细胞中20α羟基类固醇脱氢酶（20α‐HSD）对孕酮（P4）的代谢被认为是P4退出的一种机制，它伴随着子宫炎症（生理性或感染诱导）和相关转录因子的激活：NF‐кB和AP‐1，在足月和早产中很常见。我们发现，20α‐HSD蛋白在足月分娩时在人子宫肌层中显著升高，在足月和早产时在小鼠子宫中显著升高。用促炎介质脂多糖（LPS，模拟感染）和12 - O -十四酰磷- 13 -乙酸酯（TPA，模拟炎症）处理人子宫内膜细胞，诱导20α - HSD基因表达并增加20α - HSD蛋白丰度。LPS处理减少了P4向培养基中的释放，导致hTERT - HM细胞中GJA1的上调。NF‐кB /AP‐1转录因子介导LPS和TPA对20α‐HSD基因转录的影响。两种促炎刺激均诱导LPS/TPA处理的细胞中20α - HSD启动子活性，并通过抑制NF‐кB （JSH: 20µM）或AP‐1信号传导（T5224: 10µM）显著减弱。NF‐кB共识位点的删除取消了LPS介导的启动子诱导，而AP‐1位点的删除逆转了TPA介导的20α‐HSD启动子诱导。我们得出结论，炎症刺激（生理性或病理性）激活NF‐кB或AP‐1诱导20α‐HSD转录和随后的局部P4退出导致GJA1的上调和分娩前肌层的激活。
Metabolism of progesterone (P4) by the enzyme 20α hydroxysteroid dehydrogenase (20α‐HSD) in myometrial cells is postulated to be a mechanism for P4 withdrawal, which occurs concomitant to uterine inflammation (physiologic or infection‐induced) and associated activation of transcription factors: NF‐кB and AP‐1, common to term and preterm labour. We found that 20α‐HSD protein is significantly increased in human myometrium during term labour, and in mouse uterus during term and preterm labour. Treatment of human myometrial cells with the pro‐inflammatory mediators, lipopolysaccharide (LPS, mimicking infection) and 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA, mimicking inflammation), induced 20α‐HSD gene expression and increased 20α‐HSD protein abundance. LPS treatment decreased P4 release into the culture medium and resulted in up‐regulation of GJA1 in the hTERT‐HM cells. The NF‐кB /AP‐1 transcription factors mediated effects of LPS and TPA on 20α‐HSD gene transcription. Both pro‐inflammatory stimuli induced 20α‐HSD promoter activity in LPS/TPA‐treated cells which was significantly attenuated by inhibition of NF‐кB (JSH: 20 µM) or AP‐1 signalling (T5224: 10 µM). Deletion of NF‐кB consensus sites abrogated LPS‐mediated promoter induction, while removal of AP‐1 sites reversed the TPA‐mediated induction of 20α‐HSD promoter. We conclude that inflammatory stimuli (physiologic or pathologic) that activate NF‐кB or AP‐1 induce 20α‐HSD transcription and subsequent local P4 withdrawal resulting in up‐regulation of GJA1 and activation of myometrium that precedes labour.
登录
查看更多内容
影响因子：
2.9
作者：
Li, Wei;Yang, Siwen;Bocking, Alan D.
通讯作者：
Bocking, Alan D.
影响因子：
3.7
作者：
Lim S;MacIntyre DA;Lee YS;Khanjani S;Terzidou V;Teoh TG;Bennett PR
通讯作者：
Bennett PR
影响因子：
11.2
作者：
Bracken, Cameron P.;Gregory, Philip A.;Goodall, Gregory J.
通讯作者：
Goodall, Gregory J.
影响因子：
4.1
作者：
Hirabayashi, K;Ishida, M;Nishihara, M
通讯作者：
Nishihara, M
影响因子：
3
作者：
Lee C;Huang CH
通讯作者：
Huang CH