Abstract
Cytokine-activated IκB 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 physio-pathological processes. Here we report a novel role for IKKβ in maintenance of constitutive levels of the redox scavenger glutathione (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 (GCLC) and a modifier (GCLM) subunit. We find 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.
Footnotes
- Received October 1, 2009.
- Revision received February 4, 2010.
- Accepted February 12, 2010.
- The American Society for Pharmacology and Experimental Therapeutics