Pro-inflammatory signals induce 20α-HSD expression in myometrial cells: A key mechanism for local progesterone withdrawal

Metabolism of progesterone (P4) by the enzyme 20 alpha hydroxysteroid dehydrogenase (20 alpha-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-kappa B and AP-1, common to term and preterm labour. We found that 20 alpha-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 20 alpha-HSD gene expression and increased 20 alpha-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-kappa B /AP-1 transcription factors mediated effects of LPS and TPA on 20 alpha-HSD gene transcription. Both pro-inflammatory stimuli induced 20 alpha-HSD promoter activity in LPS/TPA-treated cells which was significantly attenuated by inhibition of NF-kappa B (JSH: 20 mu M) or AP-1 signalling (T5224: 10 mu M). Deletion of NF-kappa B consensus sites abrogated LPS-mediated promoter induction, while removal of AP-1 sites reversed the TPA-mediated induction of 20 alpha-HSD promoter. We conclude that inflammatory stimuli (physiologic or pathologic) that activate NF-kappa B or AP-1 induce 20 alpha-HSD transcription and subsequent local P4 withdrawal resulting in up-regulation of GJA1 and activation of myometrium that precedes labour.

Automated summary

Metabolism of progesterone by the enzyme 20 alpha hydroxysteroid dehydrogenase is a mechanism for progesterone withdrawal in myometrial cells during uterine inflammation, which involves activation of NF-kappa B and AP-1 transcription factors. Pro-inflammatory mediators like LPS and TPA induce 20 alpha-HSD gene expression and decrease P4 release, leading to up-regulation of GJA1 and myometrial activation prior to labor.