title: Suppression of the c-Jun N-terminal kinase pathway by 17beta-estradiol can preserve human islet functional mass from proinflammatory cytokine-induced destruction.
abstract: BACKGROUND
  The c-Jun N-terminal kinase (JNK) activation occurs after islet isolation, oxidative stress, and proinflammatory cytokine (PIC) exposure to beta-cells. Previous studies demonstrated that 17beta-estradiol modulates the activity of JNK; therefore we assessed the effects of 17beta-estradiol on JNK activation on islet survival and function after transplantation.
  
  
  METHODS
  Isolated human pancreatic islets were incubated with PIC and 17beta-estradiol. Viability was analyzed by a colorimetric assay, islet mass by DNA content, JNK activity by Western blots, AP-1 nuclear activity with a promoter-Luciferase AP-1 responsive construct, and c-Fos, Jun-D, and ATF-2 nuclear activities by an enzyme-linked immunosorbent assay. Islet functionality was evaluated after transplantation in streptozotocin-induced diabetic NOD-SCID mice.
  
  
  RESULTS
  The 17beta-estradiol enhanced islet viability and islet mass after exposure to PIC. A significant reduction in JNK activation occurred in islets treated with 17beta-estradiol, compared with controls, an effect partially dependent on estrogen receptors. The 17beta-estradiol induced a significant reduction in nuclear AP-1, c-fos, Jun-D, and ATF-2 activities. Animals that received 17beta-estradiol-treated islets had better islet functionality compared with saline solution-treated controls.
  
  
  CONCLUSIONS
  The 17beta-estradiol improved isolated human pancreatic islets survival after PIC exposure by inhibition of JNK. These effects were associated with reduction in JNK targets, including the nuclear activities of transcription factors AP-1, c-Jun, c-Fos, Jun-D and ATF-2, involved in apoptosis in beta-cells. The 17beta-estradiol therapy may improve the results in clinical transplantation.
authors.affiliation: Division of Transplantation, and Transplant Center, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Devin E
authors.initials: DE
authors.lastname: Eckhoff
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Smyth
authors.forename: Christopher
authors.initials: C
authors.lastname: Eckstein
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Bilbao
authors.forename: Carlton J
authors.initials: CJ
authors.lastname: Young
authors.forename: J Anthony
authors.initials: JA
authors.lastname: Thompson
authors.forename: Juan L
authors.initials: JL
authors.lastname: Contreras
mesh_terms: D051698:Activating Transcription Factor 2; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D016923:Cell Death / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D046508:Culture Techniques; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology*; D003920:Diabetes Mellitus / Q000097:blood / Q000601:surgery; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology*; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000502:physiology*; D016381:Islets of Langerhans Transplantation; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D051379:Mice; D016513:Mice, SCID; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D014022:Tissue Survival / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; C497106:Atf2 protein, mouse; D001786:Blood Glucose; D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; D018836:Inflammation Mediators; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D004958:Estradiol; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases