Journal article
Interleukin-1β Induction of NFκB Is Partially Regulated by H2O2-mediated Activation of NFκB-inducing Kinase
The Journal of biological chemistry, Vol.281(3), pp.1495-1505
01/20/2006
DOI: 10.1074/jbc.M511153200
PMID: 16286467
Abstract
Reactive oxygen species (ROS) have been demonstrated to act as second messengers in a number of signal transduction pathways, including NFkappaB. However, the mechanism(s) by which ROS regulate NFkappaB remain unclear and controversial. In the present report, we describe a mechanism whereby interleukin-1beta (IL-1beta) stimulation of NFkappaB is partially regulated by H2O2-mediated activation of NIK and subsequent NIK-mediated phosphorylation of IKKalpha. IL-1beta induced H2O2 production in MCF-7 cells and clearance of this ROS through the expression of GPx-1 reduced NFkappaB transcriptional activation by inhibiting NIK-mediated phosphorylation of IKKalpha. Although IKKalpha and IKKbeta were both involved in IL-1beta-mediated activation of NFkappaB, only the IKKalpha-dependent component was modulated by changes in H2O2 levels. Interestingly, in vitro reconstitution experiments demonstrated that NIK was activated by a very narrow range of H2O2 (1-10 microM), whereas higher concentrations (100 microM to 1 mM) inhibited NIK activity. Treatment of cells with the general Ser/Thr phosphatase inhibitor (okadaic acid) lead to activation of NFkappaB and enhanced NIK activity as a IKKalpha kinase, suggesting that ROS may directly regulate NIK through the inhibition of phosphatases. Recruitment of NIK to TRAF6 following IL-1beta stimulation was inhibited by H2O2 clearance and Rac1 siRNA, suggesting that Rac-dependent NADPH oxidase may be a source of ROS required for NIK activation. In summary, our studies have demonstrated that redox regulation of NIK by H2O2 is mechanistically important in IL-1beta induction of NFkappaB activation.
Details
- Title: Subtitle
- Interleukin-1β Induction of NFκB Is Partially Regulated by H2O2-mediated Activation of NFκB-inducing Kinase
- Creators
- Qiang LiJohn F Engelhardt
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.281(3), pp.1495-1505
- DOI
- 10.1074/jbc.M511153200
- PMID
- 16286467
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Language
- English
- Date published
- 01/20/2006
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984025358902771
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