Pretreatment with interferon-gamma protects microglia from oxidative stress via up-regulation of Mn-SOD.
Microglial cells, resident macrophage-like immune cells in the brain, are exposed to intense oxidative stress under various pathophysiological conditions. For self-defense against oxidative injuries, microglial cells must be equipped with antioxidative mechanisms. In this study, we investigated the regulation of antioxidant enzyme systems in microglial cells by interferon-gamma (IFN-gamma) and found that pretreatment with IFN-gamma for 20 h protected microglial cells from the toxicity of various reactive species such as hydrogen peroxide (H(2)O(2)), superoxide anion, 4-hydroxy-2(E)-nonenal, and peroxynitrite. The cytoprotective effect of IFN-gamma pretreatment was abolished by the protein synthesis inhibitor cycloheximide. In addition, treatment of microglial cells with both IFN-gamma and H(2)O(2) together did not protect them from the H(2)O(2)-evoked toxicity. These results imply that protein synthesis is required for the protection by IFN-gamma. Among various antioxidant enzymes such as manganese or copper/zinc superoxide dismutase (Mn-SOD or Cu/Zn-SOD), catalase, and glutathione peroxidase (GPx), only Mn-SOD was up-regulated in IFN-gamma-pretreated microglial cells. Transfection with siRNA of Mn-SOD abolished both up-regulation of Mn-SOD expression and protection from H(2)O(2) toxicity by IFN-gamma pretreatment. Furthermore, whereas the activities of Mn-SOD and catalase were up-regulated by IFN-gamma pretreatment, those of Cu/Zn-SOD and GPx were not. These results indicate that IFN-gamma pretreatment protects microglial cells from oxidative stress via selective up-regulation of the level of Mn-SOD and activity of Mn-SOD and catalase.
Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.
Xia
X
Chen
In Young
IY
Choi
Tong-Shin
TS
Chang
You Hyun
YH
Noh
Chan Young
CY
Shin
Chun-Fu
CF
Wu
Kwang Ho
KH
Ko
Won-Ki
WK
Kim
D000818:Animals; D018929:Cell Culture Techniques; D016923:Cell Death / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology; D019610:Cytoprotection / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D017628:Microglia / Q000473:pathology / Q000502:physiology*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D015854:Up-Regulation
D013481:Superoxides; D007371:Interferon-gamma; D003513:Cycloheximide; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase