title: C-Jun NH2-Terminal Kinase and p38 Inhibition Suppresses Prostaglandin E2-Stimulated Aromatase and Estrogen Receptor Levels in Human Endometriosis.
abstract: BACKGROUND
  Endometriosis is an estrogen-dependent disease. P38 and C-jun NH2-terminal kinase (JNK) inhibitors may have a therapeutic effect on endometriosis through regulation of prostaglandin E2 (PGE2)-induced estrogen metabolism.
  
  
  OBJECTIVE
  The objective of this study was to determine whether the activated MAPKs signaling pathway observed in human ectopic endometrial stromal cells (ESCs) from ovarian endometriomas influences levels of aromatase and estrogen receptor β (ERβ) protein regulated by PGE2. In turn, the effects of inhibiting MAPKs in the presence of PGE2 on estrogen production were investigated in vitro and in vivo.
  
  
  RESULTS
  Expression of aromatase and ERβ regulated by PGE2 were much higher in ESCs than eutopic ESCs from the same person. Activation of p38, JNK, ERK 1/2 and ERK 5 MAPKs by PGE2 were observed in ESCs, where PGE2-stimulated aromatase and ERβ expression mainly through p38 and JNK pathway. P38 and JNK inhibition or small interfering RNA knockdown blocked PGE2-induced aromatase and ERβ expression. PGE2 enhanced binding of downstream p38 and JNK transcription factors activating transcription factor-2 and c-Jun to aromatase and ERB promoter regions in ESCs. Moreover, treatment of endometriosis xenografts with inhibitors of p38 and JNK abrogated PGE2-amplified estradiol synthesis and xenograft growth.
  
  
  CONCLUSIONS
  PGE2 activates p38 and JNK signaling pathways, further stimulating c-Jun and activating transcription factor-2 binding to aromatase and ERB promoter regions with elevated estradiol production. Inhibition of JNK and P38 may be a potential method of treating human endometriosis.
authors.affiliation: Department of Obstetrics and Gynecology (C.Z., J.-n.X., Y.Z., H.-x.Y., Y.-f.Z., Q.X.), Peking University First Hospital, Beijing, 100034, P. R. China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zeng
authors.affiliation: Department of Obstetrics and Gynecology (C.Z., J.-n.X., Y.Z., H.-x.Y., Y.-f.Z., Q.X.), Peking University First Hospital, Beijing, 100034, P. R. China.
authors.forename: Jia-Ning
authors.initials: JN
authors.lastname: Xu
authors.affiliation: Department of Obstetrics and Gynecology (C.Z., J.-n.X., Y.Z., H.-x.Y., Y.-f.Z., Q.X.), Peking University First Hospital, Beijing, 100034, P. R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Obstetrics and Gynecology (C.Z., J.-n.X., Y.Z., H.-x.Y., Y.-f.Z., Q.X.), Peking University First Hospital, Beijing, 100034, P. R. China.
authors.forename: Hui-Xia
authors.initials: HX
authors.lastname: Yang
authors.affiliation: Department of Obstetrics and Gynecology (C.Z., J.-n.X., Y.Z., H.-x.Y., Y.-f.Z., Q.X.), Peking University First Hospital, Beijing, 100034, P. R. China.
authors.forename: Ying-Fang
authors.initials: YF
authors.lastname: Zhou
authors.affiliation: Department of Obstetrics and Gynecology (C.Z., J.-n.X., Y.Z., H.-x.Y., Y.-f.Z., Q.X.), Peking University First Hospital, Beijing, 100034, P. R. China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xue
mesh_terms: D000818:Animals; D001141:Aromatase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D004715:Endometriosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000819:agonists / Q000737:chemistry / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008819:Mice, Nude; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010049:Ovarian Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010053:Ovary / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D034622:RNA Interference; D011897:Random Allocation; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: C000600034:ESR2 protein, human; D047629:Estrogen Receptor beta; D047428:Protein Kinase Inhibitors; D004958:Estradiol; D001141:Aromatase; C561410:CYP19A1 protein, human; D048031:JNK Mitogen-Activated Protein Kinases; D048308:Mitogen-Activated Protein Kinase 14; D015232:Dinoprostone