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MnSOD and catalase transgenes demonstrate that protection of islets from oxidative stress does not alter cytokine toxicity.

Reactive oxygen species (ROS) and nitric oxide (NO) are proposed mediators of cytokine-induced beta-cell destruction in type 1 diabetes. We produced transgenic mice with increased beta-cell expression of manganese superoxide dismutase (MnSOD) and catalase. Expression of these antioxidants increased beta-cell ROS scavenging and improved beta-cell survival after treatment with different sources of ROS. MnSOD or catalase conferred protection against streptozotocin (STZ)-induced beta-cell injury. Coexpression of MnSOD and catalase provided synergistic protection against peroxynitrite and STZ. To determine the potential effect of these antioxidants on cytokine-induced toxicity, we exposed isolated islets to a cytokine mixture, including interleukin-1beta and interferon-gamma. Cytokine toxicity was measured as reduced metabolic activity after 6 days and reduced insulin secretion after 1 day. Cytokines increased ROS production, and both antioxidants were effective in reducing cytokine-induced ROS. However, MnSOD and/or catalase provided no protection against cytokine-induced injury. To understand this, the nuclear factor-kappaB (NF-kappaB) signaling cascade was investigated. Antioxidants reduced NF-kappaB activation by ROS, but none of the antioxidants altered activation by cytokines, as measured by inhibitor of kappaB phosphorylation, NF-kappaB translocation, inducible NO synthase activation, and NO production. Our data agree with previous reports that antioxidants benefit beta-cell survival against ROS damage, but they are not consistent with reports that antioxidants reduce cytokine toxicity. ROS appear to have no role in cytokine toxicity in primary beta-cells.

Pubmed ID: 15855331


  • Chen H
  • Li X
  • Epstein PN



Publication Data

May 27, 2005

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK58100
  • Agency: NHLBI NIH HHS, Id: HL075080

Mesh Terms

  • Animals
  • Base Sequence
  • Catalase
  • Cell Survival
  • Cytokines
  • DNA Primers
  • Hydrogen Peroxide
  • Islets of Langerhans
  • Mice
  • Mice, Transgenic
  • NF-kappa B
  • Oxidative Stress
  • Reverse Transcriptase Polymerase Chain Reaction
  • Streptozocin
  • Superoxide Dismutase