The non-provitarnin A carotenoid, lutein, inhibits NF-κB-dependent gene expression through redox-based regulation of the phosphatidylinositol 3-kinase/PTEN/Akt and NF-κB-inducing kinase pathways:: Role of H2O2 in NF-κB activation

Reactive oxygen species (ROS) have been implicated in the regulation of NF-kappa B activation, which plays an important role in inflammation and cell survival. However, the molecular mechanisms of ROS in NF-kappa B activation remain poorly defined. We found that the non-provitamin A carotenoid, lutein, decreased intracellular H2O2 accumulation by scavenging superoxide and H2O2 and the NF-kappa B-regulated inflammatory genes, iNOS, TNF-alpha, IL-1 beta, and cyclooxygenase-2, in lipopolysaccharide (LPS)-stimulated macrophages, Lutein inhibited LPS-induced NF-kappa B activation, which highly correlated with its inhibitory effect on LPS-induced I kappa B kinase (IKK) activation, I kappa B degradation, nuclear translocation of NF-kappa B, and binding of NF-kappa B to the kappa B motif of the iNOS promoter. This compound inhibited LPS- and H2O2-induced increases in phosphatidylinositol 3-kinase (PI3K) activity, PTEN inactivation, NF-kappa B-inducing kinase (NIK), and Akt phosphorylation, which are all upstream of IKK activation, but did not affect the interaction between Toll-like receptor 4 and MyD88 and the activation of mitogen-activated protein kinases. The NADPH oxidase inhibitor apocynin and gp91(phox) deletion reduced the LPS-induced NF-kappa B signaling pathway as lutein did. Moreover, lutein treatment and gp91(phox) deletion decreased the expressional levels of the inflammatory genes in vivo and protected mice from LPS-induced lethality. Our data Suggest that H2O2 modulates IKK-dependent NF-kappa B activation by promoting the redox-sensitive activation of the PI3K/PTEN/Akt and NIK/IKK pathways. These findings further provide new insights into the pathophysiological role of intracellular H2O2 in the NF-kappa B signal pathway and inflammatory process. Crown Copyright (C) 2008 Published by Elsevier Inc. All rights reserved.