title: Interleukin-4 and prostaglandin E2 synergistically up-regulate 3β-hydroxysteroid dehydrogenase type 2 in endometrioma stromal cells.
abstract: BACKGROUND
  Endometriosis is a chronic inflammatory disease in which immune response and production of estrogen in endometriotic tissues are involved in the development of the disease. Prostaglandin E2 (PGE2) stimulates aromatase (P450arom) expression in endometrioma stromal cells (ESCs) and increases the production of estrogens. On the other hand, an accumulating amount of evidence suggests that IL-4, a typical Th2 cytokine, plays important roles in the disease.
  
  
  OBJECTIVE
  The objective of the investigation was to study the effect of IL-4 on the expression of 3β-hydroxysteroid dehydrogenase (HSD3B2), a pivotal enzyme for estrogen production, in ESCs.
  
  
  METHODS
  ESCs were isolated from ovarian endometrioma tissues and cultured with IL-4 and PGE2. CP-690550, a Janus protein tyrosine kinase 3 inhibitor, and HSD3B2 small interfering RNA were added to the culture. Gene expression of HSD3B2 and P450arom was examined by quantitative RT-PCR. Dehydroepiandrosterone (DHEA) was added to the culture, and then the combined enzyme activity of HSD3B2, which converts DHEA to androstenedione, and P450arom, which converts androstenedione to estrone, was examined by measuring estrone concentration in the supernatants with a specific enzyme immunoassay.
  
  
  RESULTS
  IL-4 increased the expression of HSD3B2 mRNA in a dose-dependent manner. CP-650550 inhibited the IL-4-induced increase in HSD3B2 mRNA expression. PGE2 also increased the expression of HSD3B2 mRNA, and the combination of IL-4 and PGE2 synergistically increased the expression of HSD3B2 mRNA. IL-4 had no effect on the expression of P450arom mRNA, whereas PGE2 increased the expression of P450arom mRNA. Although PGE2 alone increased the production of estrone from DHEA, the combination of IL-4 and PGE2 significantly augmented the production of estrone from DHEA. The enhanced production of estrone by the combination of IL-4 and PGE2 was inhibited by CP-690550 and HSD3B2 small interfering RNA.
  
  
  CONCLUSIONS
  IL-4 in combination with PGE2 may enhance estrogen production in endometriotic tissues, implying an elaborate mechanism that Th2 immune response augments inflammation-dependent progression of the disease.
authors: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors: Yoko
authors: Y
authors: Urata
authors: Yutaka
authors: Y
authors: Osuga
authors: Ikumi
authors: I
authors: Akiyama
authors: Miwako
authors: M
authors: Nagai
authors: Gentaro
authors: G
authors: Izumi
authors: Masashi
authors: M
authors: Takamura
authors: Akiko
authors: A
authors: Hasegawa
authors: Miyuki
authors: M
authors: Harada
authors: Tetsuya
authors: T
authors: Hirata
authors: Yasushi
authors: Y
authors: Hirota
authors: Osamu
authors: O
authors: Yoshino
authors: Kaori
authors: K
authors: Koga
authors: Shiro
authors: S
authors: Kozuma
mesh_terms: D002478:Cells, Cultured; D015232:Dinoprostone / Q000494:pharmacology*; D004357:Drug Synergism; D004715:Endometriosis / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004970:Estrone / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology*; D008954:Models, Biological; D010049:Ovarian Diseases / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011375:Progesterone Reductase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D017154:Stromal Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D034741:RNA, Small Interfering; D015847:Interleukin-4; D004970:Estrone; C533068:3 beta-hydroxysteroid dehydrogenase type II; D011375:Progesterone Reductase; D015232:Dinoprostone