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

Inflammatory bowel disease is associated with increased reactive oxygen species (ROS) and decreased antioxidant response in the intestinal mucosa. Expression of the mitochondrial protein prohibitin (PHB) is also decreased during intestinal inflammation. Our previous study showed that genetic restoration of colonic epithelial PHB expression [villin-PHB transgenic (PHB Tg) mice] attenuated dextran sodium sulfate (DSS)-induced colitis/oxidative stress and sustained expression of colonic nuclear factor erythroid 2-related factor 2 (Nrf2), a cytoprotective transcription factor. This study investigated the role of Nrf2 in mediating PHB-induced protection against colitis and expression of the antioxidant response element (ARE)-regulated antioxidant genes heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase-1 (NQO-1). PHB-transfected Caco-2-BBE human intestinal epithelial cells maintained increased ARE activation and decreased intracellular ROS levels compared with control vector-transfected cells during Nrf2 knockdown by small interfering RNA. Treatment with the ERK inhibitor PD-98059 decreased PHB-induced ARE activation, suggesting that ERK constitutes a significant portion of PHB-mediated ARE activation in Caco-2-BBE cells. PHB Tg, Nrf2(-/-), and PHB Tg/Nrf2(-/-) mice were treated with DSS or 2,4,6-trinitrobenzene sulfonic acid (TNBS), and inflammation and expression of HO-1 and NQO-1 were assessed. PHB Tg/Nrf2(-/-) mice mimicked PHB Tg mice, with attenuated DSS- or TNBS-induced colitis and induction of colonic HO-1 and NQO-1 expression, despite deletion of Nrf2. PHB Tg/Nrf2(-/-) mice exhibited increased activation of ERK during colitis. Our results suggest that maintaining expression of intestinal epithelial cell PHB, which is decreased during colitis, reduces the severity of inflammation and increases colonic levels of the antioxidants HO-1 and NQO-1 via a mechanism independent of Nrf2.
AuthorsArwa S Kathiria, Mackenzie A Butcher, Jason M Hansen, Arianne L Theiss
JournalAmerican journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 304 Issue 10 Pg. G885-96 (May 15 2013) ISSN: 1522-1547 [Electronic] United States
PMID23494124 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • NF-E2 Transcription Factor, p45 Subunit
  • Nfe2 protein, mouse
  • Repressor Proteins
  • Tumor Necrosis Factor-alpha
  • prohibitin
  • RNA
  • Dextran Sulfate
  • Peroxidase
  • Luciferases
  • Heme Oxygenase-1
  • NAD(P)H Dehydrogenase (Quinone)
  • Animals
  • Antioxidant Response Elements (physiology)
  • Blotting, Western
  • Caco-2 Cells
  • Cell Line
  • Colitis (chemically induced, genetics, prevention & control)
  • Dextran Sulfate
  • Genes, Reporter
  • Heme Oxygenase-1 (metabolism)
  • Humans
  • Luciferases (metabolism)
  • MAP Kinase Signaling System (drug effects, genetics)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NAD(P)H Dehydrogenase (Quinone) (metabolism)
  • NF-E2 Transcription Factor, p45 Subunit (genetics, physiology)
  • Peroxidase (metabolism)
  • RNA (genetics, isolation & purification)
  • Real-Time Polymerase Chain Reaction
  • Repressor Proteins (genetics, metabolism, physiology)
  • Tumor Necrosis Factor-alpha (pharmacology)

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