Inhibitor of κB Kinase β Regulates Redox Homeostasis by Controlling the Constitutive Levels of Glutathione

Peng, Zhimin; Geh, Esmond; Liang, Chen; Meng, Qingxi; Fan, Yunxia; Sartor, Maureen A.; Shertzer, Howard G.; Liu, Zheng-gang; Puga, Alvaro; Xia, Ying

doi:10.1124/mol.109.061424

Cited by 37 publications

(35 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Based on the evidence that Nrf2 was just activated at 3 h of LPS exposure, and that there was a synergic effect on the increase of GCLM mRNA between LPS and Nrf2 activator sulforaphane at this time point (data not shown), it is postulated that signaling pathway other than Nrf2 was involved. NF-κB signaling was reportedly involved in the regulation of GCLM [35]. However, NF-κB inhibitor SN50 had no effect on GCLM induction at 3h of LPS exposure even though it suppressed Nrf2 signaling (Fig.5 and Fig.6).…”

Section: Discussionmentioning

confidence: 90%

Temporal changes in glutathione biosynthesis during the lipopolysaccharide-induced inflammatory response of THP-1 macrophages

Zhang

Liu

Zhou

et al. 2017

Free Radical Biology and Medicine

View full text Add to dashboard Cite

How macrophages maintain redox homeostasis in the inflammatory process, in which a large amount of oxidants are produced, remains elusive. In this study, we investigated the temporal changes in the intracellular glutathione (GSH), the master antioxidant, and the expression of glutamate cysteine ligase (GCL), the rate-limiting enzyme for GSH biosynthesis, in the inflammatory response of human macrophages (THP1 cells) to lipopolysaccharide. Intracellular GSH concentration was decreased significantly in the early phase (∼6 h) of LPS exposure, and then gradually went back to the basal level in the late phase (9∼24 h). The expression level of the catalytic subunit of GCL (GCLC) followed a similar pattern of change as GSH: its mRNA and protein levels were reduced in the early phase and then back to basal level in the late phase. In contrast, the expression of the modifier subunit of GCL (GCLM) was significantly increased in the phase of LPS exposure. Activation Nrf2, the transcription factor involved in the induction of both GCLC and GCLM, occurred at as early as 3 h after LPS exposure; whereas the activation of NF-κB occurred at as early as 30 min. Inhibition of NF-κB signaling with SN50 prevented the decrease of GCLC and inhibited Nrf2 activation in response to LPS. These data demonstrate time-dependent changes in the expression of GCL and Nrf2 signaling during the inflammatory response, and that the regulation of GCLC and GCLM might be through different pathways in this process.

show abstract

Section: Discussionmentioning

confidence: 90%

Temporal changes in glutathione biosynthesis during the lipopolysaccharide-induced inflammatory response of THP-1 macrophages

Zhang

Liu

Zhou

et al. 2017

Free Radical Biology and Medicine

View full text Add to dashboard Cite

show abstract

“…However, the generation of ROS can occur secondarily since Cd has a high affinity for thiols, such as found with glutathione [20], thus disturbing the oxidized/reduced environment of the cell. Other forms of ROS following Cd exposure may occur through Cd disruption of mitochondrial oxidative phosphorylation, or Cd induced NADPH oxidase activity [21]. To counter or minimize ROS production, Cd exposure can lead to the activation of strong antioxidative mechanisms, many of which are displayed in signaling cascades that lead to transcriptional activation of cellular defense mechanisms.…”

Section: Resultsmentioning

confidence: 99%

Cadmium and arsenic override NF-κB developmental regulation of the intestinal UGT1A1 gene and control of hyperbilirubinemia

Liu

Chen

Yueh

et al. 2016

Biochemical Pharmacology

View full text Add to dashboard Cite

Humanized UDP-glucuronosyltransferase (UGT)-1 (hUGT1) mice encode the UGT1 locus including the UGT1A1 gene. During neonatal development, delayed expression of the UGT1A1 gene leads to hyperbilirubinemia as determined by elevated levels of total serum bilirubin (TSB). We show in this report that the redox-sensitive NF-κB pathway is crucial for intestinal expression of the UGT1A1 gene and control of TSB levels. Targeted deletion of IKKβ in intestinal epithelial cells (hUGT1/IkkβΔIEC mice) leads to greater neonatal accumulation of TSB than observed in control hUGT1/IkkβΔF/F mice. The elevation in TSB levels in hUGT1/IkkβΔIEC mice correlates with a reduction in intestinal UGT1A1 expression. As TSB levels accumulate in hUGT1/IkkβΔIEC mice during the neonatal period, the increase over that observed in hUGT1/IkkβF/F mice leads to weight loss, seizures and eventually death. Bilirubin accumulates in brain tissue from hUGT1/IkkβΔIEC mice inducing an inflammatory state as shown by elevated TNFα, IL-1 β and IL-6, all of which can be prevented by neonatal induction of hepatic or intestinal UGT1A1 and lowering of TSB levels. Altering the redox state of the intestines by oral administration of cadmium or arsenic to neonatal hUGT1/IkkβF/F and hUGT1/IkkβΔIEC mice leads to induction of UGT1A1 and a dramatic reduction in TSB levels. Microarray analysis following arsenic treatment confirms upregulation of oxidation-reduction processes and lipid metabolism, indicative of membrane repair or synthesis. Our findings indicate that the redox state in intestinal epithelial cells during development is important in maintaining UGT1A1 gene expression and control of TSB levels.

show abstract

“…There are some reports that these four antioxidant genes could also be regulated through NF-κB signaling [49–52]. These reports however, are not supported by later studies based on chromatin immunoprecipitation (CHIP)-seq technology [53, 54].…”

Section: Discussionmentioning

confidence: 97%

Delayed Nrf2-regulated antioxidant gene induction in response to silica nanoparticles

Zhang

Zhou

Yuen

et al. 2017

Free Radical Biology and Medicine

View full text Add to dashboard Cite

Silica nanoparticles with iron on their surface cause the production of oxidants and stimulate an inflammatory response in macrophages. Nuclear factor erythroid-derived 2 –like factor 2 (Nrf2) signaling and its regulated antioxidant genes play critical roles in maintaining redox homeostasis. In this study we investigated the regulation of four representative Nrf2-regulated antioxidant genes; i.e., glutamate cysteine ligase (GCL) catalytic subunit (GCLC), GCL modifier subunit (GCLM), heme oxygenase 1 (HO-1), and NAD(P)H:quinone oxidoreductase-1 (NQO-1), by iron-coated silica nanoparticles (SiO2-Fe) in human THP-1 macrophages. We found that the expression of these four antioxidant genes was modified by SiO2-Fe in a time-dependent manner. At 6 h, their expression was unchanged except for GCLC, which was reduced compared with controls. At 18 h, the expression of these antioxidant genes was significantly increased compared with controls. In contrast, the Nrf2 activator sulforaphane induced all antioxidant genes at as early as 3 h. The nuclear translocation of Nrf2 occurred later than that for NF-κB p65 protein and the induction of proinflammatory cytokines (TNFα and IL-1β). NF-κB inhibitor SN50 prevented the reduction of GCLC at 6 h and abolished the induction of antioxidant genes at 18 h by SiO2-Fe, but did not affect the basal and sulforaphane-induced expression of antioxidant genes, suggesting that NF-κB signaling plays a key role in the induction of Nrf2-mediated genes in response to SiO2-Fe. Consistently, SN50 inhibited the nuclear translocation of Nrf2 caused by SiO2-Fe. In addition, Nrf2 silencing decreased the basal and SiO2-induced expression of the four reprehensive antioxidant genes. Taken together, these data indicated that SiO2-Fe induced a delayed response of Nrf2-regulated antioxidant genes, likely through NF-κB-Nrf2 interactions.

show abstract

Inhibitor of κB Kinase β Regulates Redox Homeostasis by Controlling the Constitutive Levels of Glutathione

Cited by 37 publications

References 39 publications

Temporal changes in glutathione biosynthesis during the lipopolysaccharide-induced inflammatory response of THP-1 macrophages

Temporal changes in glutathione biosynthesis during the lipopolysaccharide-induced inflammatory response of THP-1 macrophages

Cadmium and arsenic override NF-κB developmental regulation of the intestinal UGT1A1 gene and control of hyperbilirubinemia

Delayed Nrf2-regulated antioxidant gene induction in response to silica nanoparticles

Contact Info

Product

Resources

About