title: Cyclooxygenase-2 regulated by the nuclear factor-κB pathway plays an important role in endometrial breakdown in a female mouse menstrual-like model.
abstract: The role of prostaglandins (PGs) in menstruation has long been proposed. Although evidence from studies on human and nonhuman primates supports the involvement of PGs in menstruation, whether PGs play an obligatory role in the process remains unclear. Although cyclooxygenase (COX) inhibitors have been used in the treatment of irregular uterine bleeding, the mechanism involved has not been elucidated. In this study, we used a recently established mouse menstrual-like model for investigating the role of COX in endometrial breakdown and its regulation. Administration of the nonspecific COX inhibitor indomethacin and the COX-2 selective inhibitor DuP-697 led to inhibition of the menstrual-like process. Furthermore, immunostaining analysis showed that the nuclear factor (NF)κB proteins P50, P65, and COX-2 colocalized in the outer decidual stroma at 12 to 16 hours after progesterone withdrawal. Chromatin immunoprecipitation analysis showed that NFκB binding to the Cox-2 promoter increased at 12 hours after progesterone withdrawal in vivo, and real-time PCR analysis showed that the NFκB inhibitors pyrrolidine dithiocarbamate and MG-132 inhibited Cox-2 mRNA expression in vivo and in vitro, respectively. Furthermore, COX-2 and NFκB inhibitors similarly reduced endometrial breakdown, suggesting that NFκB/COX-2-derived PGs play a critical role in this process. In addition, the CD45(+) leukocyte numbers were sharply reduced following indomethacin (COX-1 and COX-2 inhibitor), DuP-697 (COX-2 inhibitor), and pyrrolidine dithiocarbamate (NFκB inhibitor) treatment. Collectively, these data indicate that NFκB/COX-2-induced PGs regulate leukocyte influx, leading to endometrial breakdown.
authors.affiliation: Reproductive Physiology Laboratory, National Research Institute for Family Planning, Beijing 100081, People’s Republic of China.
authors.forename: Xiangbo
authors.initials: X
authors.lastname: Xu
authors.forename: Xihua
authors.initials: X
authors.lastname: Chen
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Li
authors.forename: Huizi
authors.initials: H
authors.lastname: Cao
authors.forename: Cuige
authors.initials: C
authors.lastname: Shi
authors.forename: Shuo
authors.initials: S
authors.lastname: Guan
authors.forename: Shucheng
authors.initials: S
authors.lastname: Zhang
authors.forename: Bin
authors.initials: B
authors.lastname: He
authors.forename: Jiedong
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003656:Decidua / Q000378:metabolism; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007213:Indomethacin / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D008598:Menstruation / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011759:Pyrrolidines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013859:Thiocarbamates / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology
chemical_list: D016861:Cyclooxygenase Inhibitors; D007976:Leupeptins; D016328:NF-kappa B; D011759:Pyrrolidines; D013859:Thiocarbamates; D013876:Thiophenes; C020972:pyrrolidine dithiocarbamic acid; C064874:DuP 697; D051546:Cyclooxygenase 2; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D007213:Indomethacin