title: Leptin promotes HLA-G expression on placental trophoblasts via the MEK/Erk and PI3K signaling pathways.
abstract: BACKGROUND
  The development of the human haemochorial placenta requires complex regulatory mechanisms to protect invasive trophoblast cells from cytotoxic responses elicited by maternal immune cells. Leptin, the adipocyte derived hormone encoded by the Lep gene, is synthesized by placental trophoblasts and exerts pleiotropic effects on the immune system, including the promotion of inflammation and the activation of T cell responses.
  
  
  METHODS
  To address its possible involvement in the modulation of maternal immune responses during pregnancy, we investigated the effect of leptin on the expression of the class Ib histocompatibility antigen HLA-G as one of the chief immunosuppressive strategies used by trophoblast cells.
  
  
  RESULTS
  In vitro incubation of the trophoblast derived Swan 71 and JEG-3 cell lines with 25-50 ng/ml recombinant leptin significantly boosted HLA-G mRNA and protein expression, and this effect was abrogated upon pharmacological inhibition of the PI3K-Akt and MEK-Erk signaling pathways. A similar stimulatory effect of leptin was observed in term placental tissue explants, though 10-fold higher doses were required for stimulation. Further, JEG-3 cells treated with a leptin antisense oligodeoxynucleotide displayed decreased HLA-G expression levels, which were partially recovered by addition of stimulating doses of exogenous hormone. Immunofluorescence and qPCR analysis confirmed leptin biosynthesis in placental tissue, further showing that invasive extravillous trophoblast cells were a main source of this hormone during the first trimester of normal pregnancies.
  
  
  CONCLUSIONS
  Taken together, our results show that leptin acts as an autocrine/paracrine signal promoting HLA-G expression in placental trophoblasts suggesting an important role in the regulation of immune evasion mechanisms at the fetal maternal interface.
authors: Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, IQUIBICEN CONICET, Buenos Aires, Argentina.
authors: G
authors: G
authors: Barrientos
authors: Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, IQUIBICEN CONICET, Buenos Aires, Argentina.
authors: A
authors: A
authors: Toro
authors: Charité Center 12 Internal Medicine and Dermatology, Reproductive Medicine Research Group, Medicine University Berlin, Germany.
authors: P
authors: P
authors: Moschansky
authors: Laboratoire d'Hormonologie, Department of Gynaecology and Obstetrics, Geneva, Switzerland.
authors: M
authors: M
authors: Cohen
authors: Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Derqui-Buenos Aires, Argentina.
authors: M G
authors: MG
authors: Garcia
authors: Charité Center 12 Internal Medicine and Dermatology, Reproductive Medicine Research Group, Medicine University Berlin, Germany.
authors: M
authors: M
authors: Rose
authors: Hospital Nacional Profesor Alejandro Posadas, Buenos Aires, Argentina.
authors: B
authors: B
authors: Maskin
authors: Departamento de Bioquímica Médica y Biología Molecular, Hospital Universitario Virgen Macarena, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain.
authors: V
authors: V
authors: Sánchez-Margalet
authors: Charité Center 12 Internal Medicine and Dermatology, Reproductive Medicine Research Group, Medicine University Berlin, Germany. Electronic address: sandra.blois@charite.de.
authors: S M
authors: SM
authors: Blois
authors: Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, IQUIBICEN CONICET, Buenos Aires, Argentina. Electronic address: cvarone@qb.fcen.uba.ar.
authors: C L
authors: CL
authors: Varone
mesh_terms: D000328:Adult; D002460:Cell Line; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D020868:Gene Silencing; D059951:HLA-G Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020738:Leptin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020319:Oligodeoxyribonucleotides, Antisense; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D010929:Placentation / Q000187:drug effects; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011263:Pregnancy Trimester, Third; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D046509:Tissue Culture Techniques; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*
chemical_list: D059951:HLA-G Antigens; D020738:Leptin; D020319:Oligodeoxyribonucleotides, Antisense; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D058539:Phosphatidylinositol 3-Kinase
keywords: HLA-G; Leptin; Placenta; Signal transduction