title: RANKL promotes the growth of decidual stromal cells in an autocrine manner via CCL2/CCR2 interaction in human early pregnancy.
abstract: OBJECTIVE
  Receptor-activator of NF-κB ligand (TNFSF11, also known as RANKL) and its receptor RANK are essential regulators on bone remodeling, mammary gland development and hormone-associated breast cancer development. However, the expression pattern and role of RANKL/RANK axis in decidual stromal cells (DSCs) are unclear in human early pregnancy.
  
  
  METHODS
  We analyzed RANKL/RANK expression in DSCs by real-time PCR, immunhistochemistry, enzyme-linked immunosorbent assay (ELISA) and flow cytometry, respectively. Then BrdU cell proliferation assay, flow cytometry assay and ELISA were performed to investigate the effect of recombinant human RANKL and DSCs-derived RANKL on the proliferation, apoptosis, chemokine (C-C motif) ligand 2 (CCL2) secretion, C-C chemokine receptor type 2 (CCR2) and other target proteins expression in DSCs in vitro, respectively.
  
  
  RESULTS
  Here we show that DSCs co-express RANKL/RANK. Not only recombinant human (rh) RANKL but also the DSC-secreted RANKL stimulate proliferation and anti-apoptosis, and elevate CCL2 secretion and CCR2 expression of DSCs. Furthermore, the stimulatory effects on the proliferation, anti-apoptosis and the expression of Bcl-2 and Ki67 and inhibitory signaling on Fas ligand (FasL) in DSCs induced by RANKL can be partly reversed by the way of blocking CCL2 and or CCR2.
  
  
  CONCLUSIONS
  Our results have revealed that RANKL/RANK signal promotes Bcl-2 and Ki67 and decreases FasL expression, and further as a positive regulator for stimulating the proliferation and growth of DSCs through up-regulating CCL2/CCR2 signal, which finally contributes to the establishment and maintenance of physiological pregnancy.
authors.affiliation: Laboratory for Reproductive Immunology, Hospital & Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, 413 Zhaozhou Rd., Shanghai 200011, China.
authors.forename: Y-H
authors.initials: YH
authors.lastname: Meng
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.forename: L-B
authors.initials: LB
authors.lastname: Liu
authors.forename: J
authors.initials: J
authors.lastname: Shao
authors.forename: K-K
authors.initials: KK
authors.lastname: Chang
authors.forename: M-R
authors.initials: MR
authors.lastname: Du
authors.forename: L-P
authors.initials: LP
authors.lastname: Jin
authors.forename: M-Q
authors.initials: MQ
authors.lastname: Li
authors.forename: D-J
authors.initials: DJ
authors.lastname: Li
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000502:physiology*; D003656:Decidua / Q000166:cytology / Q000378:metabolism; D053222:Fas Ligand Protein / Q000096:biosynthesis; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000096:biosynthesis; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D053245:RANK Ligand / Q000096:biosynthesis / Q000494:pharmacology*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000096:biosynthesis; D054390:Receptors, CCR2 / Q000502:physiology*; D017154:Stromal Cells / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation
chemical_list: C515334:CCR2 protein, human; D018932:Chemokine CCL2; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D019394:Ki-67 Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D054390:Receptors, CCR2; C505686:TNFRSF11A protein, human