Variations in IB1/JIP1 Expression Regulate Susceptibility of Beta-Cells to Cytokine-Induced Apoptosis Irrespective of C-Jun NH2-terminal Kinase Signaling

Diabetes. 2003 Oct;52(10):2497-502. doi: 10.2337/diabetes.52.10.2497.

Abstract

We previously reported that interleukin-1beta (IL-1beta) alone does not cause apoptosis of beta-cells, whereas when combined with gamma-interferon (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha), it exerts a distinct apoptotic effect. Studies in beta-cell lines indicated that IL-1beta reduced expression of islet brain (IB)-1/JNK interacting protein (JIP)-1, a JNK scaffold protein with antiapoptotic action. We examined whether variations in IB1/JIP-1 expression in purified primary beta-cells affect their susceptibility to cytokine-induced apoptosis. Exposure to IL-1beta for 24 h decreased cellular IB1/JIP-1 content by 66 +/- 17%; this IL-1beta effect was maintained in the presence of TNF-alpha + IFN-gamma, which did not influence IB1/JIP-1 levels by themselves. Addition of IL-1beta to TNF-alpha + IFN-gamma increased apoptosis from 20 +/- 2% to 59 +/- 5%. A similar increase in TNF-alpha + IFN-gamma-induced apoptosis was produced by adenoviral expression of antisense IB1/JIP-1 and was not further enhanced by addition of IL-1beta, indicating that IL-1beta-mediated suppression of IB1/JIP-1 in beta-cells increases their susceptibility to cytokine-induced apoptosis. However, adenovirally mediated overexpression of IB1/JIP-1 also potentiated TNF-alpha + IFN-gamma-induced apoptosis, suggesting that the antiapoptotic effect of IB1/JIP-1 depends on well-defined cellular levels. We conclude that the IB1/JIP-1 level in beta-cells can control their susceptibility to apoptosis independent of JNK signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Carrier Proteins / metabolism*
  • Cells, Cultured
  • Cytokines / pharmacology*
  • Drug Administration Schedule
  • Drug Combinations
  • Drug Synergism
  • Gene Transfer Techniques
  • Humans
  • Interferon-gamma / genetics
  • Interferon-gamma / pharmacology
  • Interleukin-1 / administration & dosage
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / physiology*
  • JNK Mitogen-Activated Protein Kinases
  • Male
  • Mitogen-Activated Protein Kinases / metabolism*
  • Nuclear Proteins / metabolism*
  • Rats
  • Rats, Wistar
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / pharmacology
  • Signal Transduction / physiology*
  • Trans-Activators / metabolism*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Cytokines
  • Drug Combinations
  • Interleukin-1
  • MAPK8IP1 protein, human
  • Mapk8ip1 protein, rat
  • Nuclear Proteins
  • Recombinant Proteins
  • Trans-Activators
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases