title: Inhibition of dual specificity phosphatase-2 by hypoxia promotes interleukin-8-mediated angiogenesis in endometriosis.
abstract: OBJECTIVE
  How does hypoxia-mediated down-regulation of dual specificity phosphatase-2 (DUSP2) promote endometriotic lesion development?
  
  
  CONCLUSIONS
  Inhibition of DUSP2 by hypoxia enhances endometriotic lesion growth via promoting interleukin-8 (IL-8)-dependent angiogenesis.
  
  
  BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  This study was conducted in primary human cell cultures and a mouse model, therefore may not fully reflect the situation in vivo.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  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.
authors.affiliation: Department of Physiology, College of Medicine and Hospital, National Cheng Kung University, Tainan 70101, Taiwan.
authors.forename: Kuei-Yang
authors.initials: KY
authors.lastname: Hsiao
authors.affiliation: Department of Physiology, College of Medicine and Hospital, National Cheng Kung University, Tainan 70101, Taiwan.
authors.forename: Ning
authors.initials: N
authors.lastname: Chang
authors.affiliation: Department of Physiology, College of Medicine and Hospital, National Cheng Kung University, Tainan 70101, Taiwan.
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Lin
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine and Hospital, National Cheng Kung University, Tainan 70101, Taiwan.
authors.forename: Yo-Hua
authors.initials: YH
authors.lastname: Li
authors.affiliation: Department of Physiology, College of Medicine and Hospital, National Cheng Kung University, Tainan 70101, Taiwan Department of Obstetrics and Gynecology, College of Medicine and Hospital, National Cheng Kung University, Tainan 70101, Taiwan mhwu68@mail.ncku.edu.tw.
authors.forename: Meng-Hsing
authors.initials: MH
authors.lastname: Wu
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D054641:Dual Specificity Phosphatase 2 / Q000037:antagonists & inhibitors*; D004715:Endometriosis / Q000378:metabolism / Q000473:pathology*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D009389:Neovascularization, Pathologic; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D016209:Interleukin-8; C517032:DUSP2 protein, human; D054641:Dual Specificity Phosphatase 2
keywords: angiogenesis; dual specificity phosphatase 2; endometriosis; hypoxia; interleukin-8