PT - JOURNAL ARTICLE AU - Zhimin Peng AU - Esmond Geh AU - Liang Chen AU - Qinghang Meng AU - Yunxia Fan AU - Maureen Sartor AU - Howard G. Shertzer AU - Zheng-Gang Liu AU - Alvaro Puga AU - Ying Xia TI - Inhibitor of κB Kinase β Regulates Redox Homeostasis by Controlling the Constitutive Levels of Glutathione AID - 10.1124/mol.109.061424 DP - 2010 May 01 TA - Molecular Pharmacology PG - 784--792 VI - 77 IP - 5 4099 - http://molpharm.aspetjournals.org/content/77/5/784.short 4100 - http://molpharm.aspetjournals.org/content/77/5/784.full SO - Mol Pharmacol2010 May 01; 77 AB - Cytokine-activated inhibitor of κB kinase β (IKKβ) is a key mediator of immune and inflammatory responses, but recent studies suggest that IKKβ is also required for tissue homeostasis in physiopathological processes. Here we report a novel role for IKKβ in maintenance of constitutive levels of the redox scavenger GSH. Inactivation of IKKβ by genetic or pharmacological means results in low cellular GSH content and marked reduction of redox potential. Similar to Ikkβ(−/−) cells, Tnfr1(−/−) and p65(−/−) cells are also GSH-deficient. As a consequence, cells deficient in IKKβ signaling are extremely susceptible to toxicity caused by environmental and pharmacological agents, including oxidants, genotoxic agents, microtubule toxins, and arsenic. GSH biosynthesis depends on the activity of the rate-limiting enzyme glutamate-cysteine ligase (GCL), consisting of a catalytic subunit (GCLC) and a modifier subunit (GCLM). We found that loss of IKKβ signaling significantly reduces basal NF-κB activity and decreases binding of NF-κB to the promoters of Gclc and Gclm, leading to reduction of GCLC and GCLM expression. Conversely, overexpression of GCLC and GCLM in IKKβ-null cells partially restores GSH content and prevents stress-induced cytotoxicity. We suggest that maintenance of GSH is a novel physiological role of the IKKβ-NF-κB signaling cascade to prevent oxidative damage and preserve the functional integrity of the cells.U.S. Government work not protected by U.S. copyright