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- Title
Inhibition of dual specificity phosphatase-2 by hypoxia promotes interleukin-8-mediated angiogenesis in endometriosis.
- Authors
Hsiao, Kuei-Yang; Chang, Ning; Lin, Shih-Chieh; Li, Yo-Hua; Wu, Meng-Hsing
- Abstract
STUDY QUESTION How does hypoxia-mediated down-regulation of dual specificity phosphatase-2 (DUSP2) promote endometriotic lesion development? SUMMARY ANSWER Inhibition of DUSP2 by hypoxia enhances endometriotic lesion growth via promoting interleukin-8 (IL-8)-dependent angiogenesis. WHAT IS KNOWN ALREADY Angiogenesis is a prerequisite for the development of endometriosis. DUSP2 is down-regulated in endometriotic stromal cells in a hypoxia inducible factor-1α-dependent manner. Down-regulation of DUSP2 contributes to the pathological process of endometriosis. STUDY DESIGN, SIZE, DURATION A laboratory study recruiting 20 patients of reproductive age with endometriosis and normal menstrual cycles, and an autoimplant-induced mouse model of endometriosis using 13 mice in a 28-day treatment. PARTICIPANTS/MATERIALS, SETTING, METHODS IL-8 mRNA levels were assayed in endometrial stromal cells maintained in normoxic or hypoxic (1% O2) conditions, with or without DUSP2 knockdown. Promoter activity and chromatin immunoprecipitation (ChIP) assays were conducted to characterize the regulation of IL-8 by DUSP2. Conditioned media from cells maintained in normoxic or hypoxic conditions, and cells with/without DUSP2 knockdown were collected to investigate the angiogenic capacity using an in vitro tube formation assay. Reparixin, an IL-8 receptor blocker, was administered to investigate the role of IL-8 in hypoxia-mediated angiogenesis and the development of endometriotic-like lesions in an autotransplanted mouse model. MAIN RESULTS AND THE ROLE OF CHANCE IL-8 mRNA was increased by both hypoxia and DUSP2 knockdown in endometrial stromal cells in an extracellular signal-regulated protein kinase-dependent manner (P < 0.05 versus control). Promoter activity and ChIP assays demonstrated that expression of IL-8 was regulated by CCAAT/enhancer binding protein α (P < 0.05 versus control). Furthermore, conditioned media collected from hypoxia-exposed or DUSP2 knockdown endometrial stromal cells promoted tube formation, which was abolished by co-treatment with reparixin (P < 0.05 versus control). Results from the autotransplanted mouse model demonstrated that number of blood vessels and size of endometriotic-like lesions were markedly reduced in recipient mice treated with reparixin (P < 0.05 versus control). LIMITATIONS, REASONS FOR CAUTION This study was conducted in primary human cell cultures and a mouse model, therefore may not fully reflect the situation in vivo. WIDER IMPLICATIONS OF THE FINDINGS This is the first study to highlight the potential application of an IL-8 receptor blocker as a therapeutic target to treat endometriosis. This study demonstrates IL-8 as a key angiogenic factor regulated by hypoxia/DUSP2, which suggests an alternative mechanism through which hypoxia may promote angiogenesis. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by the National Science Council of Taiwan (NSC101-2314-B-006-043-MY2). The author declares that there is no conflict of interest.
- Subjects
PHOSPHATASES; HYPOXEMIA; INTERLEUKIN-8; ENDOMETRIOSIS; NEOVASCULARIZATION; HYPOXIA-inducible factors; THERAPEUTICS
- Publication
Human Reproduction, 2014, Vol 29, Issue 12, p2747
- ISSN
0268-1161
- Publication type
Article
- DOI
10.1093/humrep/deu255