The non-provitamin 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

Ji Hee Kim, Hee Jun Na, Chun Ki Kim, Ji Yoon Kim, Kwon Soo Ha, Hansoo Lee, Hun Taeg Chung, Ho Jeong Kwon, Young Guen Kwon, Young Myeong Kim

Research output: Contribution to journalArticle

150 Citations (Scopus)

Abstract

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

Original languageEnglish
Pages (from-to)885-896
Number of pages12
JournalFree Radical Biology and Medicine
Volume45
Issue number6
DOIs
Publication statusPublished - 2008 Sep 15

    Fingerprint

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology (medical)

Cite this