Suppression of the c-Jun N-terminal kinase pathway by 17β-estradiol can preserve human islet functional mass from proinflammatory cytokine-induced destruction

Academic Article


  • Background. The c-Jun N-terminal kinase (JNK) activation occurs after islet isolation, oxidative stress, and proinflammatory cytokine (PIC) exposure to β-cells. Previous studies demonstrated that 17β-estradiol modulates the activity of JNK; therefore we assessed the effects of 17β-estradiol on JNK activation on islet survival and function after transplantation. Methods. Isolated human pancreatic islets were incubated with PIC and 17β-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 17β-estradiol enhanced islet viability and islet mass after exposure to PIC. A significant reduction in JNK activation occurred in islets treated with 17β-estradiol, compared with controls, an effect partially dependent on estrogen receptors. The 17β-estradiol induced a significant reduction in nuclear AP-1, c-fos, Jun-D, and ATF-2 activities. Animals that received 17β-estradiol-treated islets had better islet functionality compared with saline solution-treated controls. Conclusions. The 17β-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 β-cells. The 17β-estradiol therapy may improve the results in clinical transplantation.
  • Authors

    Published In

  • Surgery  Journal
  • Digital Object Identifier (doi)

    Pubmed Id

  • 12503312
  • Author List

  • Eckhoff DE; Smyth CA; Eckstein C; Bilbao G; Young CJ; Thompson JA; Contreras JL
  • Start Page

  • 169
  • End Page

  • 179
  • Volume

  • 134
  • Issue

  • 2