Nrf2 is not required for epithelial prohibitin-dependent attenuation of experimental colitis

Kathiria, Arwa S.; Butcher, Mackenzie; Hansen, Jason M.; Theiss, Arianne L.

doi:10.1152/ajpgi.00327.2012

Cited by 18 publications

(18 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Multiple animal models of colitis also exhibit decreased PHB expression [16, 20, 21]. Transgenic mice overexpressing PHB in IECs are protected from experimental colitis and exhibit less oxidative stress in the colon [20, 22]. This is in agreement with emerging data that suggest a role of PHB in protection against oxidative stress-induced injury in multiple cells types [23-27].…”

Section: Introductionsupporting

confidence: 65%

“…Expression of PHB is decreased in uninvolved and inflamed epithelium in IBD patients compared to healthy control patients [9, 16]. Multiple animal models of colitis also exhibit decreased PHB expression [16, 20, 21]. Transgenic mice overexpressing PHB in IECs are protected from experimental colitis and exhibit less oxidative stress in the colon [20, 22].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Prohibitin 1 modulates mitochondrial function of Stat3

Han

Souza

et al. 2014

Cellular Signalling

Self Cite

View full text Add to dashboard Cite

Mitochondrial dysfunction in intestinal epithelial cells (IEC) is thought to precede the onset of inflammatory bowel diseases (IBD). Expression of Prohibitin 1 (PHB), a mitochondrial protein required for optimal electron transport chain (ETC) activity, is decreased in mucosal biopsies during active and inactive IBD. In addition to its activities as a transcription factor, Signal Transducer and Activator of Transcription 3 (Stat3) resides in the mitochondria of cells where phosphorylation at S727 is required for optimal ETC activity and protects against stress-induced mitochondrial dysfunction. Here, we show that PHB overexpression protects against mitochondrial stress and apoptosis of cultured IECs induced by TNFα, which is a pro-inflammatory cytokine involved in IBD pathogenesis. Expression of pS727-Stat3 dominant negative eliminates protection by PHB against TNFα-induced mitochondrial stress and apoptosis. PHB interacts with pS727-Stat3 in the mitochondria of cultured IECs and in colonic epithelium from wild-type mice. Our data suggest a protective role of PHB that is dependent on pS727-Stat3 to prevent mitochondrial dysfunction in IECs. Reduced levels of PHB during IBD may be an underlying factor promoting mitochondrial dysfunction of the intestinal epithelium.

show abstract

Section: Introductionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Prohibitin 1 modulates mitochondrial function of Stat3

Han

Souza

et al. 2014

Cellular Signalling

Self Cite

View full text Add to dashboard Cite

show abstract

“…Male mice (12 weeks of age) with a global deficiency in Nrf2 (Nrf2 KO; kind gift from Thomas Kensler) 19 and wild-type (WT) littermates (C57BL/6J background) were used in all experiments. All experimental procedures were approved by the Institute for Animal Care and Use Committee at Emory University School of Medicine and conformed to the Guide for the Care and Use of Laboratory Animals , published by the National Institutes of Health (NIH Publication No.…”

Section: Methodsmentioning

confidence: 99%

Sodium Sulfide Attenuates Ischemic-Induced Heart Failure by Enhancing Proteasomal Function in an Nrf2-Dependent Manner

Shimizu

Nicholson

Lambert

et al. 2016

Circ: Heart Failure

Self Cite

View full text Add to dashboard Cite

Background Therapeutic strategies aimed at increasing hydrogen sulfide (H2S) levels exert cytoprotective effects in various models of cardiovascular injury. However, the underlying mechanism(s) responsible for this protection remain to be fully elucidated. Nuclear-factor-E2-related factor-2 (Nrf2) is a cellular target of H2S and facilitator of H2S-mediated cardioprotection following acute myocardial infarction. Here, we tested the hypothesis that Nrf2 mediates the cardioprotective effects of H2S therapy in the setting of heart failure (HF). Methods and Results Mice (12 weeks of age) deficient in Nrf2 (Nrf2 KO; C57BL/6J background) and wild-type (WT) littermates were subjected to ischemic-induced HF. WT mice treated with H2S in the form of sodium sulfide (Na2S) displayed enhanced Nrf2 signaling, improved left-ventricular function, and less cardiac hypertrophy following the induction of HF. In contrast, Na2S therapy failed to provide protection against HF in Nrf2 KO mice. Studies aimed at evaluating the underlying cardioprotective mechanisms found that Na2S increased the expression of proteasome subunits, resulting in an increase proteasome activity and a reduction in the accumulation of damaged proteins. In contrast, Na2S therapy failed to enhance the proteasome and failed to attenuate the accumulation of damaged proteins in Nrf2 KO mice. Additionally, Na2S failed to improve cardiac function when the proteasome was inhibited. Conclusions These findings indicate that Na2S therapy enhances proteasomal activity and function during the development of heart failure in an Nrf2-dependent manner and that this enhancement leads to attenuation in cardiac dysfunction.

show abstract

“…For example, the expression of HO-1 was found to be dependent on Nrf2 signaling in intestinal epithelial cells (34)(35)(36). However, tumor necrosis factor alpha (TNF-␣) was shown to increase HO-1 protein levels in the Caco-2 cell line, and Nrf2 suppression did not affect TNF-␣-induced HO-1 protein expression in these cells (37). Although MAPK signaling is important for HO-1 expression (11,38,39), there is no evidence of BFT-induced MAPK and NF-B activation leading to HO-1 expression.…”

Section: Discussionmentioning

confidence: 99%

Bacteroides fragilis Enterotoxin Upregulates Heme Oxygenase-1 in Intestinal Epithelial Cells via a Mitogen-Activated Protein Kinase- and NF-κB-Dependent Pathway, Leading to Modulation of Apoptosis

Rho

Jeon

et al. 2016

Infect Immun

View full text Add to dashboard Cite

Enterotoxigenic Bacteroides fragilis (ETBF) is associated with noninvasive diarrheal diseases (1, 2), inflammatory bowel diseases (1), and colorectal cancers (3-5). B. fragilis enterotoxin (BFT), a virulence factor of ETBF, is responsible for these diseases (1). BFT interacts with a single layer of intestinal epithelial cells and can provoke signals that induce mucosal inflammation (1, 6-9).In mammalian cells, two genetically distinct isozymes of heme oxygenase (HO) have been clearly identified. HO-1 is inducible, whereas HO-2 is constitutively expressed. HO-1 catalyzes the degradation of free heme into carbon monoxide, biliverdin, and free iron (10, 11). Within mammalian cells, biliverdin reductase converts biliverdin to bilirubin. Pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS), lipoteichoic acid, and peptidoglycan, as well as several proinflammatory cytokines, can induce HO-1 expression (12). Upregulated HO-1 expression can lead to adaptive immune responses that protect cells from immunopathogenesis or stress damage (12, 13). In addition, HO-1 expression is involved in clearance of pathogenic bacteria and downregulation of inflammatory responses. For example, HO-1 deficiency not only results in inadequate pathogen clearance (14) but also promotes the development of necrotizing enterocolitis-like intestinal injury in mice (15). HO-1 and HO-1-induced carbon monoxide can ameliorate intestinal inflammation through promotion of bacterial clearance (16). The HO-1/carbon monoxide pathway also suppresses Toll-like receptor 4 (TLR4) signaling, leading to downregulation of proinflammatory signaling induced by stimulation with LPS (17). Based on these findings, we hypothesized that the induction of HO-1 may regulate inflammatory responses induced by BFT. However, there are no reports regarding BFT-induced HO-1 expression.Signals from transcription factors, including nuclear factor-B (NF-B), activator protein-1 (AP-1), and NF-E2-related factor 2 (Nrf2, or nuclear factor [erythroid-derived 2]-like 2 [NFE2L2]), regulate the expression of HO-1 (11). Stimulation of intestinal epithelial cells with BFT can activate NF-B and AP-1 signaling (6)(7)(8)(9)(18)(19)(20). We have previously demonstrated that exposure of intestinal epithelial cells to BFT results in delayed apoptosis, suggesting that protection of cells after BFT stimulation is related to the generation of signals that activate or suppress mucosal inflammation (21). These observations raise the possibility that signaling molecules that regulate HO-1 expression may be activated in BFTexposed cells. However, there is no evidence that BFT-induced signaling results in HO-1 induction in intestinal epithelial cells. We therefore investigated HO-1 induction in response to stimulation of intestinal epithelial cells with BFT. We found that a signaling pathway involving p38 mitogen-activated protein kinases (MAPKs)-IB kinase (IKK)-NF-B in intestinal epithelial cells is required for HO-1 induction following exposure to BFT.

show abstract

Nrf2 is not required for epithelial prohibitin-dependent attenuation of experimental colitis

Cited by 18 publications

References 58 publications

Prohibitin 1 modulates mitochondrial function of Stat3

Prohibitin 1 modulates mitochondrial function of Stat3

Sodium Sulfide Attenuates Ischemic-Induced Heart Failure by Enhancing Proteasomal Function in an Nrf2-Dependent Manner

Bacteroides fragilis Enterotoxin Upregulates Heme Oxygenase-1 in Intestinal Epithelial Cells via a Mitogen-Activated Protein Kinase- and NF-κB-Dependent Pathway, Leading to Modulation of Apoptosis

Contact Info

Product

Resources

About