In addition to blocking acid secretion, the proton pump inhibitor (PPI) lansoprazole induces heme oxygenase-1 (HO-1), leading to cytoprotective and anti-inflammatory actions; however, the underlying mechanism for induction has remained unknown. In this issue, Takagi et al., examine the possible role of the redox-sensitive nuclear factor E2-related factor 2 (Nrf-2) in mediating the induction. The inhibitory Keap-1 protein mediates Nrf2 factor degradation in the cytoplasm, and Nrf2 is released during oxidative stress and migrates to the nucleus where it activates antioxidant-responsive element-dependent gene expression. It was found that lansoprazole induces increased HO-1 expression in cultured gastric epithelial cells (RGM-1), leading to inhibited chemokine expression following stimulation. The increased HO-1 expression was attenuated with Nrf2-small interference RNA transfection, and electrophoretic mobility assays showed Nrf2 nuclear localization and response element binding. It was also found that HO-1 induction was mediated by extracellular signal-regulated kinase phosphorylation and that the Keap1 protein was oxidized after lansoprazole treatment. Collectively, these studies reveal greater detail on the mechanisms surrounding PPI-mediated HO-1 induction and the role of Keap-1 oxidation and Nrf-2 activation.
See article at J Pharmacol Exp Ther 2009, 331:255–264.
- © 2009 by the American Society for Pharmacology and Experimental Therapeutics