TY - JOUR AU - Engelhardt, John F. AB -

Reactive oxygen species (ROS) have been demonstrated to act as second messengers in a number of signal transduction pathways, including NFκB. However, the mechanism(s) by which ROS regulate NFκB remain unclear and controversial. In the present report, we describe a mechanism whereby interleukin-1β (IL-1β) stimulation of NFκB is partially regulated by H2O2-mediated activation of NIK and subsequent NIK-mediated phosphorylation of IKKα. IL-1β induced H2O2 production in MCF-7 cells and clearance of this ROS through the expression of GPx-1 reduced NFκB transcriptional activation by inhibiting NIK-mediated phosphorylation of IKKα. Although IKKα and IKKβ were both involved in IL-1β-mediated activation of NFκB, only the IKKα-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 μm), whereas higher concentrations (100 μm to 1 mm) inhibited NIK activity. Treatment of cells with the general Ser/Thr phosphatase inhibitor (okadaic acid) lead to activation of NFκB and enhanced NIK activity as a IKKα kinase, suggesting that ROS may directly regulate NIK through the inhibition of phosphatases. Recruitment of NIK to TRAF6 following IL-1β 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-1β induction of NFκB activation.

TI - Interleukin-1β Induction of NFκB Is Partially Regulated by H2O2-mediated Activation of NFκB-inducing Kinase * JF - Journal of Biological Chemistry DO - 10.1074/jbc.m511153200 DA - 2006-01-20 UR - https://www.deepdyve.com/lp/american-society-for-biochemistry-and-molecular-biology/interleukin-1-induction-of-nf-b-is-partially-regulated-by-h2o2-HzvAFeW0Fx SP - 1495 EP - 1505 VL - 281 IS - 3 DP - DeepDyve ER -