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
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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