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.