MnSOD and Catalase Transgenes Demonstrate That Protection of Islets From Oxidative Stress Does Not Alter Cytokine Toxicity

Abstract

Reactive oxygen species (ROS) and nitric oxide (NO) are proposed mediators of cytokine-induced β-cell destruction in type 1 diabetes. We produced transgenic mice with increased β-cell expression of manganese superoxide dismutase (MnSOD) and catalase. Expression of these antioxidants increased β-cell ROS scavenging and improved β-cell survival after treatment with different sources of ROS. MnSOD or catalase conferred protection against streptozotocin (STZ)-induced β-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-1β and interferon-γ. 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-κB (NF-κB) signaling cascade was investigated. Antioxidants reduced NF-κB activation by ROS, but none of the antioxidants altered activation by cytokines, as measured by inhibitor of κB phosphorylation, NF-κB translocation, inducible NO synthase activation, and NO production. Our data agree with previous reports that antioxidants benefit β-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 β-cells.