Selenite activates caspase-independent necrotic cell death in Jurkat T cells and J774.2 macrophages by affecting mitochondrial oxidant generation.

Abstract

Sodium selenite, a common dietary form of selenium, is recognized as essential in animal and human nutrition. Mechanisms regulating the inflammatory response of the immune system involve regulation of apoptosis and control of reactive oxygen species (ROS) production. In this study, the effect of sodium selenite on ROS production and cell-death rates in macrophages and T cells was investigated. Exposing Jurkat T cells or J774.2 macrophages to >5 micro M sodium selenite induced cell death. In both Jurkat T cells and J774.2 macrophages, rapid loss of the cell's capacity to generate dichlorofluorescein-sensitive ROS preceded cell death. The main cellular source of ROS was found to be the mitochondria electron-transfer chain. DEVDase activity in the cells remained unchanged and even decreased with time, as well as DNA fragmentation level, which was almost unaffected, indicating cell death with necrotic characteristics. tert-Butyl hydroperoxide at a concentration of 5 micro M was beneficial in attenuating the rate of cell death. The superoxide scavenger Tiron was tested for its ability to protect the cells against selenium. Tiron completely protected the J774.2 macrophage cell line against selenium and attenuated the cell death effect in Jurkat T cells. In the presence of the superoxide dismutase-mimicking compound tempol, selenium's macrophage-killing effect was inhibited. Therefore, our results show that, at least in vitro, selenite induces changes in the balance between mitochondrial superoxide and hydrogen peroxide production, which can facilitate cell death in immune system cells. This may be one mechanism by which selenium down-regulates the immune system's inflammatory response and protects against overproduction of peroxides.