Roles of Reactive Oxygen Species, NF-κB, and Peroxiredoxins in Glycochenodeoxycholic Acid-Induced Rat Hepatocytes Death

Chu, Sang Hui; Lee-Kang, Jihee; Lee, Kweon-Haeng; Lee, Kyung‐Eun

doi:10.1159/000071244

Cited by 19 publications

(7 citation statements)

References 30 publications

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“…The finding that no bile acid was capable of activating NF‐κB in this study is at odds with an earlier report that certain nontoxic bile acids are potent NF‐κB inducers 12. One factor that might explain the discrepancy is that Schoemaker et al treated hepatocytes with relatively low concentrations of bile acids (50 μmol/L), whereas investigators who achieved positive results used higher concentrations 12, 13. Another issue is that Schoemaker et al used primary hepatocytes for their study.…”

Section: Commentscontrasting

confidence: 99%

What doesn't kill you makes you stronger: How hepatocytes survive prolonged cholestasis

Maher

2004

Hepatology

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The goals of the current study are to examine the extent and mechanisms of apoptosis in cholestatic liver injury and to explore the role of the transcription factor nuclear factor-kappa B (NF-kappaB) in protection against bile acid-induced apoptosis. Cholestatic liver injury was induced by bile duct ligation in Wistar rats. Furthermore, primary cultures of rat hepatocytes were exposed to glycochenodeoxycholic acid (GCDCA), tauroursodeoxycholic acid, taurochenodeoxycholic acid, and to cytokines. Apoptosis was determined by TUNEL staining, active caspase-3 staining, and by activation of caspase-8, caspase-9, and caspase-3. Limited hepatocyte apoptosis and increased expression of NF-kappaB-regulated anti-apoptotic genes A1 and cIAP2 were detected in cholestatic rat liver specimens. Bcl-2 expression was restricted to bile duct epithelium. In contrast to taurochenodeoxycholic acid and tauroursodeoxycholic acid, GCDCA induced apoptosis in a Fas-associated protein with death domain-independent pathway in hepatocytes. Although bile acids do not activate NF-kappaB, NF-kappaB activation by cytokines (induced during cholestasis) protected against GCDCA-induced apoptosis in vitroby upregulating A1 and cIAP2. GCDCA induces apoptosis in a mitochondria-controlled pathway in which caspase-8 is activated in a Fas-associated protein with death domain-independent manner. However, bile acid-induced apoptosis in cholestasis is limited. This could be explained by cytokine-induced activation of NF-kappaB-regulated antiapoptosis genes like A1 and cIAP2.

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Section: Commentscontrasting

confidence: 99%

What doesn't kill you makes you stronger: How hepatocytes survive prolonged cholestasis

Maher

2004

Hepatology

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“…Thus, we surmise that NF-B plays its role in fine tuning of Prdx6 expression, depending upon the cellular environment and cell types. However, Chu et al (88) have predicted a negative role for NF-B in antioxidant gene regulation. Recently, Gallagher and Phelan (31) showed an increase of Prdx6 expression in the presence of NF-B inhibitor in H2.35 mouse hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

Loss of NF-κB Control and Repression of Prdx6 Gene Transcription by Reactive Oxygen Species-driven SMAD3-mediated Transforming Growth Factor β Signaling

Fatma

Kubo

Takamura

et al. 2009

Journal of Biological Chemistry

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Activation of transforming growth factor ␤ (TGF␤) in response to increased reactive oxygen species (ROS) leads to pathophysiology of cells/tissues by overmodulation of gene transcription. PRDX6 plays a rheostat role in regulating gene transcription by controlling cellular ROS in maintaining homeostasis; thus, fine tuning of Prdx6 expression is required to optimize ROS levels. Ϫ/Ϫ or Prdx6 Ϫ/Ϫ cells was moderately increased by disruption of NF-B sites, suggesting the role of NF-B in tuning of Prdx6 expression. Findings revealed a mechanism of repression and regulation of PRDX6 expression in cells facing stress or aging and provided clues for antioxidant(s)-based new approaches in preventing ROS-driven deleterious signaling. PRDX6 (peroxiredoxin 6) is a member of an emerging peroxiredoxin family that has GSH peroxidase as well as acidic Ca 2ϩ -independent phospholipase A2 activities (1-7). The peroxiredoxins function in concert to detoxify reactive oxygen species (ROS) 2 and play a cytoprotective role by removing ROS and by limiting ROS levels regulating cell survival signaling (1, 3, 4, 6, 8, 9 -11). The unique ability to regulate signaling and to maintain phospholipid turnover distinguishes PRDX6 from the other five peroxiredoxins (PRDX1 to -5). This molecule is widely expressed, occurring in high levels in the liver, lung, eye lens, and keratinocytes (1, 2, 10, 12-18), whereas reduced expression of PRDX6 can lead to cell death and tissue degeneration (10, 11, 15, 19 -22). PRDX6 has been implicated in maintenance of blood vessel integrity in wounded skin (23, 24) and in development and progression of several diseases, including oxidative-induced cataractogenesis (25), psoriasis (12, 26) atherosclerosis (22), and Parkinsonian dementia (27). Accumulating evidence indicates that expression levels of PRDX6 contribute to pathophysiology of cells and tissues. Several studies have reported decreases in antioxidant levels and increases in ROS levels, leading to a decline in a number of physiological functions because of overmodulation of ROS-mediated gene expression and activation of such factors as TGF␤ and NF-B, hallmarks of the aging process and age-associated degenerative diseases (28 -30). However, given the role of ROS as a mediator of normal or redox signaling, we believe that optimal regulation of Prdx6 expression may require fine tuning to avoid overshooting the desired beneficial effects to the point of perturbing the delicate redox balance essential to maintenance of normal cellular function. Recently, using targeted inactivation of the Prdx6 gene, we reported activation and expression of TGF␤ and TGF␤-mediated suppression of Prdx6 mRNA and protein (1,4,5,31), suggesting that this molecule may have a role in repression of Prdx6 transcription. Quantification by staining with H2DCF-DA established a higher prevalence of ROS in these cells. Also, the activation of TGF␤ in Prdx6-deficient cells was associated with ROS and inhibited by PRDX6 overexpression or MnTBAP, a superoxide dismutase mimetic and a known ROS...

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“…In addition, this was accompanied by activation of transcriptional factor NFκB. ROS is a potent activator of NFκB (Chu et al, 2003, and this activation has been associated with ROS‐induced cell death (Jones et al, 2000). Our comparative proteomic analysis demonstrated that silencing Prdx1 led to down‐regulation of IκB‐ε, which is consistent with increased NFκB activity as IκB‐ε sequesters NFκB in the cytoplasm and inhibits its activation.…”

Section: Discussionmentioning

confidence: 99%

Comparative proteomic analysis identifies protein disulfide isomerase and peroxiredoxin 1 as new players involved in embryonic interdigital cell death

Shan

Tang

Cai³

et al. 2005

Developmental Dynamics

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In this study, we used comparative proteomics to identify proteins that were involved in the regulation of interdigital cell death. The protein profiles of embryonic day (E) 12.5 and 13.5 mouse hindlimb interdigital tissues were compared to identify proteins that were differentially expressed. The interdigital cells are irreversibly committed to programmed cell death (PCD) at E13.5, whereas they are developmentally plastic at E12.5. We established that protein disulfide isomerase (PDI) expression was up-regulated at E13.5, while peroxiredoxin 1 (Prdx1) expression was down-regulated at this time point. Semiquantitative reverse transcriptase-polymerase chain reaction and Western blot analyses confirmed the data obtained from the two-dimensional electrophoresis gels. Furthermore, we were able to up-regulate PDI expression by manipulating the E12.5 interdigital tissues to die during culture, although this up-regulation was not possible when cell survival was promoted. In addition, we could inhibit interdigital cell death and expression of proapoptotic genes (Bmp-4 and Bambi) by treating interdigital tissues with PDI antibodies and bacitracin (a PDI enzyme inhibitor). These findings suggested that PDI was involved in the activation and maintenance of interdigital cell death. Conversely, we determined that Prdx1 expression was maintained when interdigital cultures were manipulated to survive but down-regulated when the cultures were permitted to die. The result suggested that Prdx1 was involved in maintaining interdigital cell survival. However, we were unable to induce interdigital cell death by means of RNA interference-mediated silencing of Prdx1 expression, indicating that Prdx1 down-regulation is not sufficient for PCD to occur. Proteomic analysis of the Prdx1 knock-down cells revealed that the level of NF-kappaB inhibitor epsilon (IB) was dramatically reduced. Furthermore, we found an increase in NFB activation and reactive oxygen species (ROS) levels in the cytoplasm as a result of Prdx1 knockdown. We also found that silencing Prdx1 made the interdigital cells more susceptible to ROS-induced cell death. Taken together, our study identifies two new players in interdigital cell death and highlights that PCD is regulated by a delicate balance of proapoptotic and survival-promoting activities. Developmental Dynamics 233:266 -281, 2005.

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Roles of Reactive Oxygen Species, NF-κB, and Peroxiredoxins in Glycochenodeoxycholic Acid-Induced Rat Hepatocytes Death

Cited by 19 publications

References 30 publications

What doesn't kill you makes you stronger: How hepatocytes survive prolonged cholestasis

What doesn't kill you makes you stronger: How hepatocytes survive prolonged cholestasis

Loss of NF-κB Control and Repression of Prdx6 Gene Transcription by Reactive Oxygen Species-driven SMAD3-mediated Transforming Growth Factor β Signaling

Comparative proteomic analysis identifies protein disulfide isomerase and peroxiredoxin 1 as new players involved in embryonic interdigital cell death

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