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

Diabetes. 2005 May;54(5):1437-46. doi: 10.2337/diabetes.54.5.1437.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Base Sequence
  • Catalase / genetics
  • Catalase / metabolism*
  • Cell Survival / drug effects
  • Cytokines / toxicity*
  • DNA Primers
  • Hydrogen Peroxide / pharmacology
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / enzymology
  • Islets of Langerhans / immunology
  • Islets of Langerhans / physiology*
  • Mice
  • Mice, Transgenic
  • NF-kappa B / metabolism
  • Oxidative Stress
  • Reverse Transcriptase Polymerase Chain Reaction
  • Streptozocin / pharmacology
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism*

Substances

  • Cytokines
  • DNA Primers
  • NF-kappa B
  • Streptozocin
  • Hydrogen Peroxide
  • Catalase
  • Superoxide Dismutase