A Novel Isoform of Microphthalmia-Associated Transcription Factor Inhibits IL-8 Gene Expression in Human Cervical Stromal Cells

被引:17
作者
Li, Xiang-Hong [1 ]
Kishore, A. Hari [1 ]
Dao, Doan [1 ]
Zheng, Weiming [1 ]
Roman, Christopher A. [2 ]
Word, R. Ann [1 ]
机构
[1] Univ Texas SW Med Ctr Dallas, Div Reprod Endocrinol & Urogynecol, Dept Obstet & Gynecol, Dallas, TX 75390 USA
[2] Suny Downstate Med Ctr, Dept Cell Biol, New York, NY 11203 USA
基金
美国国家卫生研究院;
关键词
HUMAN UTERINE CERVIX; CULTURED MAST-CELLS; MI/MI GENOTYPE; PRETERM LABOR; FACTOR FAMILY; MUTANT MICE; FACTOR MITF; INTERLEUKIN-8; PREGNANCY; PARTURITION;
D O I
10.1210/me.2009-0320
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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. (Molecular Endocrinology 24: 1512-1528, 2010)
引用
收藏
页码:1512 / 1528
页数:17
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