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.
Chen
Hainan
H
Department of Pediatrics, University of Louisville, 570 South Preston St., Baxter Research Building, Suite 304, Louisville, Kentucky 40202, USA.
Li
Xiaoyan
X
Epstein
Paul N
PN
D000818:Animals; D001483:Base Sequence; D002374:Catalase / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000633:toxicity*; D017931:DNA Primers; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013311:Streptozocin / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*
D016207:Cytokines; D017931:DNA Primers; D016328:NF-kappa B; D013311:Streptozocin; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase