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Published on: May 21, 2018
Selenium attenuates expression of MnSOD and uncoupling protein 2 in J774.2 macrophages: molecular mechanism for its
Shani Shilo1, Michal Aharoni-Simon, Oren Tirosh
1The School of Nutritional Sciences, Institute of Biochemistry, Food Science and Nutrition, Faculty of Agricultural, Food and Environmental Quality Sciences, The Hebrew University of Jerusalem, Rehovet, Israel.
Abstract:
Selenium can activate cell death. However, the mechanism of action is not yet fully defined. We hypothesized that selenium may impede mitochondrial superoxide dismutation to H2O2 and O2, leading to cell death in macrophages and that this effect may be relevant to antiinflammatory treatment by selenium. In this study, the mechanism of action of selenium was investigated in nonactivated and activated (immune-stimulated) J774.2 macrophages. Sodium selenite treatment decreased dichlorodihydrofluorescein-reacting intracellular reactive oxygen species (ROS) (mainly peroxides and hydroxyl radicals), with no correlation to glutathione peroxidase activity. However, selenite decreased the transcription and expression of manganese superoxide dismutase (MnSOD) and uncoupling protein 2 (UCP2). This cellular effect was due to inhibition of specificity protein-1 (Sp1) binding to its DNA binding site. Following immune stimulation of macrophages using lipopolysaccharides plus interferon-gamma, MnSOD was up-regulated. Activated macrophages showed higher mitochondrial membrane potential, intracellular ROS levels, and cellular resistance to cell death. Selenite treatment attenuated all of these parameters. Selenite prevented nuclear factor-kappaB (NF-kappaB) activation as a mechanism of its inhibitory activity on MnSOD expression in the immune-stimulated cells. In addition, overexpression of human MnSOD protected against death induced by selenite treatment. It is therefore concluded that selenium at high nanomolar to low micromolar concentrations shifts the balance between inflammatory response and cell death toward the latter, through a direct effect on the transcription factors Sp1 and NF-kappaB, and down-regulation of MnSOD and UCP2.
Insights
Selenium induces cell death by inhibiting mitochondrial superoxide dismutase (MnSOD) and uncoupling protein 2 (UCP2) expression, impacting inflammatory responses and cell survival pathways.
Area of Science:
- Biochemistry
- Cell Biology
- Immunology
Background:
- Selenium's cell death-inducing properties are known but not fully understood.
- The role of selenium in modulating inflammatory responses requires further investigation.
Purpose of the Study:
- To elucidate the mechanism by which selenium induces cell death in macrophages.
- To investigate selenium's impact on mitochondrial function and inflammatory signaling pathways.
Main Methods:
- Investigated selenium's effects on reactive oxygen species (ROS) and gene expression in J774.2 macrophages.
- Analyzed the impact of immune stimulation (lipopolysaccharides plus interferon-gamma) on macrophage responses to selenium.
- Assessed the role of transcription factors Sp1 and NF-kappaB, and mitochondrial proteins MnSOD and UCP2.
Main Results:
- Sodium selenite decreased intracellular ROS, MnSOD, and UCP2 expression by inhibiting Sp1 binding.
- Immune-stimulated macrophages exhibited increased MnSOD, ROS, and cell death resistance.
- Selenite treatment attenuated these effects in activated macrophages, preventing NF-kappaB activation and reducing MnSOD expression.
Conclusions:
- Selenium shifts the balance towards cell death by down-regulating MnSOD and UCP2 via Sp1 and NF-kappaB.
- Overexpression of MnSOD confers protection against selenite-induced cell death.
- Selenium's anti-inflammatory effects may be linked to its ability to induce cell death in activated macrophages.
