Oxidative Stress Transiently Decreases the IKK Complex (IKKα, β, and γ), an Upstream Component of NF-κB Signaling, after Transient Focal Cerebral Ischemia in Mice

Abstract

Nuclear factor-jB (NF-jB) has a central role in coordinating the expression of a wide variety of genes that control cerebral ischemia. Although there has been intense research on NF-jB, its mechanisms in the ischemic brain have not been clearly elucidated. We investigated the temporal profile of NFjB-related genes using a complementary DNA array method in wild-type mice and human copper/ zinc-superoxide dismutase transgenic (SOD1 Tg) mice that had low-level reactive oxygen species (ROS) by scavenging superoxide. Our DNA array showed that IjB kinase (IKK) complex (IKKa, b, and c) mRNA in the wild-type mice was decreased as early as 1 h after reperfusion, after 30 mins of transient focal cerebral ischemia (tFCI). In contrast, tFCI in the SOD1 Tg mice caused an increase in the IKK complex. The IKK complex protein levels were also drastically decreased at 1 h in the wildtype mice, but did not change in the SOD1 Tg mice throughout the 7 days. Electrophoretic mobility shift assay revealed activation of NF-jB DNA binding after tFCI in the wild-type mice. Nuclear factorjB activation occurred at the same time, as did the phosphorylation and degradation of the inhibitory protein IjBa. However, SOD1 prevented NF-jB activation, and phosphorylation and degradation of IjBa after tFCI. Superoxide production and ubiquitinated protein in the SOD1 Tg mice were also lower than in the wild-type mice after tFCI. These results suggest that ROS are implicated in transient downregulation of IKKa, b, and c in cerebral ischemia.

Biphasic Role of Nuclear Factor-k B on Cell Survival and COX-2 Expression in SOD1 Tg Astrocytes after Oxygen Glucose Deprivation

“…after transient focal cerebral ischemia (Song et al, 2005). Thus, the data from our current study showing lower levels of phosphorylated IkBa-and NF-kB-binding activity after hypoxic and reoxygenation injury might also be due to lower superoxide levels in the SOD1 Tg astrocytes.…”

Characterization of a novel curcumin analog P1 as potent inhibitor of the NF-κB signaling pathway with distinct mechanisms

“…However, there is evidence that ROS may also inhibit npg the NF-κB signaling pathway [46] . It has been reported that cysteine residue 179 in the activation loop of IKK-β [47,48] and that several conserved cysteine residues in the DNA-binding loop of the NF-κB/Rel proteins [49][50][51] may be targeted by ROS. P1 may inhibit NF-κB activation by modifying Cys-179 of IKK-β, as the inhibitory effects of P1 on NF-κB activity were abolished by the expression of mutant IKK-β, which contains alanine at residue 179 rather than cysteine ( Figure 5F).…”

Aldo-keto reductase 1 family B7 is the gene induced in response to oxidative stress in the livers of Long-Evans Cinnamon rats

“…In contrast, cuprous ions did not induce the luciferase activity of p6.0 kb-AKR-Luc, suggesting that copper signaling may not directly affect its transcriptional activity. However, several studies demonstrated that cellular damage by copper mediates NF-κB signaling and that the copper chelating agent thiomolibdate suppresses NF-κB activation (48)(49)(50)(51). Based on these studies and our present observations from the transfection assays, we speculate that the Akr1b7 gene is mainly induced by NF-κB activation, which is mediated through copper accumulation in the hepatocytes of LEC rats.…”