Pro‐inflammatory signals induce 20α‐HSD expression in myometrial cells: A key mechanism for local progesterone withdrawal
Autor: | Stephen J. Lye, Sam Mesiano, Lubna Nadeem, Oksana Shynlova, Rathesh Balendran, Anna Dorogin |
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Rok vydání: | 2021 |
Předmět: |
Adult
Lipopolysaccharides 0301 basic medicine endocrine system medicine.medical_specialty Lipopolysaccharide Inflammation labour Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Pregnancy Transcription (biology) Internal medicine Gene expression medicine Animals Humans 20α‐HSD progesterone metabolism Hydroxysteroid dehydrogenase Transcription factor Progesterone 20-alpha-Hydroxysteroid Dehydrogenase chemistry.chemical_classification myometrium NF‐кB NF-kappa B Myometrium preterm birth Original Articles Cell Biology AP‐1 Transcription Factor AP-1 HEK293 Cells 030104 developmental biology Endocrinology Enzyme chemistry Connexin 43 030220 oncology & carcinogenesis Premature Birth Tetradecanoylphorbol Acetate Molecular Medicine Female Original Article medicine.symptom |
Zdroj: | Journal of Cellular and Molecular Medicine |
ISSN: | 1582-4934 1582-1838 |
Popis: | 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. |
Databáze: | OpenAIRE |
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