Hypoxia and PGE2 regulate MiTF-CX during cervical ripening

Annavarapu Hari Kishore, Xiang Hong Li, R. Ann Word

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The mechanisms by which the cervix remains closed during the massive uterine expansion of pregnancy are unknown. IL-8 is important for recruitment of immune cells into the cervical stroma, matrix remodeling, and dilation of the cervix during labor. Previously, we have shown that several cytokine genes transcriptionally repressed in the cervix during gestation are activated during cervical ripening and dilation. IL-8 gene expression is repressed in cervical stromal cells during pregnancy by the transcription factor microphthalmia-associated transcription factor (MiTF-CX). Here, we tested the hypothesis that hypoxia and the transcription factor hypoxia inducible factor-1α (HIF-1α) may regulate MiTF-CX and cervical ripening. Using tissues from women during pregnancy before and after cervical ripening, we show that, during cervical ripening, HIF-1α was stabilized and relocalized to the nucleus. Further, we found that hypoxia and two hypoxia mimetics that stabilize HIF-1α activated the transcriptional repressor differentiated embryo chondrocyte-expressed gene 1, which bound to sites in the MiTF-CX promoter crucial for its positive autoregulation. Ectopic overexpression of MiTF-CX abrogated hypoxia-induced upregulation of IL-8 gene expression. We also show that activation of HIF-1α induced cyclooxygenase- 2 and that prostaglandin E2 repressed MiTF-CX.We conclude that hypoxia and stabilization of the transcription factor HIF-1α result in up-regulation of differentiated embryo chondrocyteexpressed gene 1, loss of MiTF, and absence of MiTF binding to the IL-8 promoter, which in turn leads to up-regulation of IL-8 gene expression. Hypoxia also up-regulated cyclooxygenase-2, leading to prostaglandin E2-mediated loss of MiTF in cervical stromal cells. The results support a pivotal role for hypoxia and HIF-1α in the cervical ripening process during pregnancy.

Original languageEnglish (US)
Pages (from-to)2031-2045
Number of pages15
JournalMolecular Endocrinology
Volume26
Issue number12
DOIs
StatePublished - Dec 1 2012

Fingerprint

Cervical Ripening
Hypoxia-Inducible Factor 1
Dinoprostone
Interleukin-8
Pregnancy
Microphthalmia-Associated Transcription Factor
Cervix Uteri
Up-Regulation
Cyclooxygenase 2
Stromal Cells
Gene Expression
Dilatation
Transcription Factors
Embryonic Structures
Genes
Chondrocytes
Hypoxia
Homeostasis
Cytokines

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Hypoxia and PGE2 regulate MiTF-CX during cervical ripening. / Kishore, Annavarapu Hari; Li, Xiang Hong; Ann Word, R.

In: Molecular Endocrinology, Vol. 26, No. 12, 01.12.2012, p. 2031-2045.

Research output: Contribution to journalArticle

Kishore, Annavarapu Hari ; Li, Xiang Hong ; Ann Word, R. / Hypoxia and PGE2 regulate MiTF-CX during cervical ripening. In: Molecular Endocrinology. 2012 ; Vol. 26, No. 12. pp. 2031-2045.
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