title: 2-Methoxyestradiol: A Hormonal Metabolite Modulates Stimulated T-Cells Function and proliferation.
abstract: BACKGROUND
  2-Methoxyestradiol (2ME2) is an endogenous metabolite of estrogen that is nonestrogenic and has been studied in cancer as an antimitotic agent that is beneficial by its selectivity for cancer cells without toxicity to nonmalignant cells. Because the effect of 2ME2 in a transplant rejection setting remains unknown, we hypothesized that 2ME2 can inhibit stimulated T-cell function.
  
  
  METHODS
  Human peripheral blood mononuclear cells (PBMCs) were cultured and pretreated with 2ME2 before stimulation. The cultured medium was collected for enzyme-linked immunosorbent assays, and whole-cell lysates were collected for Western immunoblotting. Proliferation and apoptosis assays were performed and analyzed by means of flow cytometry.
  
  
  RESULTS
  Tumor necrosis factor -α and interferon-γ cytokine production in 2ME2-treated stimulated PBMCs were modestly reduced relative to control samples. T-cell proliferation was blunted by treatment with 2ME2, and a decrease in apoptosis correlated with a decrease in caspase-9 activity. Additionally, 2ME2 was able to block stress-induced senescence caused by stimulation of T-cells.
  
  
  CONCLUSIONS
  2ME2 is a hormone-based therapy that blunts stimulated T-cell proliferation and does not induce apoptosis or stress-induced senescence. Stimulated T-cells treated with 2ME2 are still able to produce normal levels of cytokines. Therefore, 2ME2 may lead to an oral immunomodulatory adjunct therapy with a low side effect profile for individuals undergoing transplantation.
authors: Division of Cardiac Surgery, Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada; Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada.
authors: J G Y
authors: JG
authors: Luc
authors: Division of Cardiology, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors: R
authors: R
authors: Paulin
authors: Division of Cardiac Surgery, Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada; Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada.
authors: J Y
authors: JY
authors: Zhao
authors: Division of Cardiac Surgery, Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada; Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada; Alberta Transplant Institute, Li Ka Shing Centre for Health Research, Edmonton, Alberta, Canada; Canadian National Transplant Research Program, Canada.
authors: D H
authors: DH
authors: Freed
authors: Division of Cardiology, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors: E D
authors: ED
authors: Michelakis
authors: Division of Cardiac Surgery, Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada; Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada; Alberta Transplant Institute, Li Ka Shing Centre for Health Research, Edmonton, Alberta, Canada; Canadian National Transplant Research Program, Canada. Electronic address: jayan@ualberta.ca.
authors: J
authors: J
authors: Nagendran
mesh_terms: D000077584:2-Methoxyestradiol; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects*
chemical_list: D004958:Estradiol; D000077584:2-Methoxyestradiol