The transcription factor nuclear factor kappaB (NF-kappaB) is a critical regulator of inflammation and immunity and is negatively regulated via S-glutathionylation. The inhibitory effect of S-glutathionylation is overcome by glutaredoxin-1 (Grx1), which under physiological conditions catalyzes deglutathionylation and enhances NF-kappaB activation. The mechanisms whereby expression of the Glrx1 gene is regulated remain unknown. Here we examined the role of NF-kappaB in regulating activation of Glrx1. Transgenic mice that express a doxycycline-inducible constitutively active version of inhibitory kappaB kinase-beta (CA-IKKbeta) demonstrate elevated expression of Grx1. Transient transfection of CA-IKKbeta also resulted in significant induction of Grx1. A 2-kb region of the Glrx1 promoter that contains two putative NF-kappaB binding sites was activated by CA-IKKbeta, RelA/p50, and lipopolysaccharide (LPS). Chromatin immunoprecipitation experiments confirmed binding of RelA to the promoter of Glrx1 in response to LPS. Stimulation of C10 lung epithelial cells with LPS caused transient increases in Grx1 mRNA expression and time-dependent increases in S-glutathionylation of IKKbeta. Overexpression of Grx1 decreased S-glutathionylation of IKKbeta, prolonged NF-kappaB activation, and increased levels of proinflammatory mediators. Collectively, this study demonstrates that the Glrx1 gene is positively regulated by NF-kappaB and suggests a feed-forward mechanism to promote NF-kappaB signaling by decreasing S-glutathionylation.
|Journal||Free Radical Biology and Medicine|
|Publication status||Published - 1 Jan 2011|
Aesif, S. W., Kuipers, I., van der Velden, J., Tully, J. E., Guala, A. S., Anathy, V., Sheely, J. I., Reynaert, N. L., Wouters, E. F. M., van der Vliet, A., & Janssen-Heininger, Y. M. W. (2011). Activation of the glutaredoxin-1 gene by nuclear factor B enhances signaling. Free Radical Biology and Medicine, 51(6), 1249-1257. https://doi.org/10.1016/j.freeradbiomed.2011.06.025