title: Progesterone induces human leukocyte antigen-g expression in vascular endothelial and smooth muscle cells.
abstract: BACKGROUND
  Human leukocyte antigen-G (HLA-G) expression in heart transplant patients has been negatively associated with acute cellular rejection and cardiac allograft vasculopathy. We assessed HLA-G expression in vascular human endothelial and smooth muscle cell cultures to determine if future therapeutic agents can be targeted toward inducing HLA-G expression to protect against allograft rejection and vasculopathy.
  
  
  RESULTS
  Human coronary artery endothelial, aortic endothelial, and coronary artery smooth muscle cell cultures were exposed to cytokines (interferon-gamma or interleukin-10), hypoxia/reoxygenation stress, immunosuppressive agents (cyclosporine, sirolimus, or tacrolimus), or progesterone. HLA-G was not expressed by untreated, normoxic cells. Furthermore, maximal doses of interferon-gamma, interleukin-10, cyclosporine, sirolimus, or tacrolimus, as well as exposure to hypoxia/reoxygenation, failed to induce HLA-G expression. HLA-G, which has previously not been detected in adult vascular endothelial and smooth muscle cells, was detected by enzyme-linked immunosorbent assay and flow cytometry in human coronary artery endothelial, human coronary aortic endothelial, and human coronary artery smooth muscle cultures after incubation with progesterone in a dose-dependent manner (P<0.001) with no change in cellular proliferation ability or viability. This effect was partially blocked in the presence of mifepristone, a progesterone receptor antagonist (human coronary artery endothelial: 48.8+/-15.6%; human coronary aortic endothelial: 59.5+/-9.5%; human coronary artery smooth muscle: 59.8+/-9.8% of control; P<0.05). Progesterone-induced HLA-G expression was not protective against hypoxia/reoxygenation injury.
  
  
  CONCLUSIONS
  HLA-G is not expressed at baseline in vascular endothelial and smooth muscle cells but can be induced by exposure to progesterone. Although tightly regulated, induction of HLA-G expression in these cells may represent a promising and novel therapeutic strategy to protect against rejection and cardiac allograft vasculopathy after heart transplantation.
authors.affiliation: MSc, NCSB 11C-1201, Toronto General Hospital, 585 University Avenue, Toronto, Ontario, Canada.
authors.forename: Rohit
authors.initials: R
authors.lastname: Sheshgiri
authors.forename: Vivek
authors.initials: V
authors.lastname: Rao
authors.forename: Laura C
authors.initials: LC
authors.lastname: Tumiati
authors.forename: Rong
authors.initials: R
authors.lastname: Xiao
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Prodger
authors.forename: Mitesh
authors.initials: M
authors.lastname: Badiwala
authors.forename: Clifford
authors.initials: C
authors.lastname: Librach
authors.forename: Diego H
authors.initials: DH
authors.lastname: Delgado
mesh_terms: D001011:Aorta / Q000166:cytology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology; D016207:Cytokines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006680:HLA Antigens / Q000096:biosynthesis*; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis*; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D015735:Mifepristone / Q000494:pharmacology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000502:physiology; D011374:Progesterone / Q000008:administration & dosage / Q000494:pharmacology*; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors
chemical_list: D016207:Cytokines; D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; D006727:Hormone Antagonists; D007166:Immunosuppressive Agents; D011980:Receptors, Progesterone; D015735:Mifepristone; D011374:Progesterone