A novel isoform of microphthalmia-associated transcription factor inhibits IL-8 gene expression in human cervical stromal cells

Xiang Hong Li, A. Hari Kishore, Doan Dao, Weiming Zheng, Christopher A. Roman, R. Ann Word

Research output: Contribution to journalArticle

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Abstract

Cervical ripening during pregnancy is a profound change in cervix structure and function characterized by increases in the proinflammatory cytokine IL-8 and dissolution of the cervical extracellular matrix. Relatively little is known about the molecular mechanisms that underlie these events. Here, we report identification of a novel isoform of micropthalmia-associated transcription factor in human cervical stromal cells (MiTF-CX) that is down-regulated 12-fold during cervical ripening and that represses expression of IL-8. Ectopic expression of MiTF-CX in human cervical stromal cells resulted in substantial suppression of endogenous IL-8 mRNA and protein expression, whereas expression of dominant negative MiTF-CX mutants with impaired DNA binding resulted in dramatic increases in IL-8 production. Gel shift, reporter gene, and chromatin immunoprecipitation assays revealed one strong binding site (E-box -397 CACATG-391) in the human IL-8 promoter that was crucial for mediating transcriptional repression by MiTF-CX. Moreover, we show that MiTF-CX expression in the cervix was itself positively autoregulated via two E-box motifs within a 2.1-kb promoter fragment. We therefore propose that maintenance of cervical competency during pregnancy is an active process maintained through suppression of IL-8 by the transcription factor MiTF-CX. During cervical ripening, loss of MiTF-CX would result in significant up-regulation of IL-8 mRNA and protein synthesis, thereby leading to recruitment and activation of leukocytes within the cervix and dissolution of the extracellular matrix.

Original languageEnglish (US)
Pages (from-to)1512-1528
Number of pages17
JournalMolecular Endocrinology
Volume24
Issue number8
DOIs
StatePublished - Aug 1 2010

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ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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