Reactive oxygen species (ROS) have been implicated in the regulation of NF-κB activation, which plays an important role in inflammation and cell survival. However, the molecular mechanisms of ROS in NF-κB 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-κB-regulated inflammatory genes, iNOS, TNF-α, IL-1β, and cyclooxygenase-2, in lipopolysaccharide (LPS)-stimulated macrophages. Lutein inhibited LPS-induced NF-κB activation, which highly correlated with its inhibitory effect on LPS-induced IκB kinase (IKK) activation, IκB degradation, nuclear translocation of NF-κB, and binding of NF-κB to the κB motif of the iNOS promoter. This compound inhibited LPS- and H2O2-induced increases in phosphatidylinositol 3-kinase (PI3K) activity, PTEN inactivation, NF-κB-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 gp91phox deletion reduced the LPS-induced NF-κB signaling pathway as lutein did. Moreover, lutein treatment and gp91phox 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-κB 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-κB signal pathway and inflammatory process. Crown
|Number of pages||12|
|Journal||Free Radical Biology and Medicine|
|Publication status||Published - 2008 Sep 15|
Bibliographical noteFunding Information:
This work was supported by the Vascular System Research Center Grant from the Korea Science and Engineering Foundation and the Korea Science and Engineering Foundation grant funded by the Korea government (MOST) (M10642140004–06N4214–0040).
All Science Journal Classification (ASJC) codes
- Physiology (medical)