Activation of the glutaredoxin-1 gene by nuclear factor kappa B enhances signaling

作者：Aesif Scott W; Kuipers Ine; van der Velden Jos; Tully Jane E; Guala Amy S; Anathy Vikas; Sheely Juliana I; Reynaert Niki L; Wouters Emiel F M; van der Vliet Albert; Janssen Heininger Yvonne M W^*

来源：Free Radical Biology and Medicine, 2011, 51(6): 1249-1257.

DOI：10.1016/j.freeradbiomed.2011.06.025

• S-glutathionylation
• Nuclear factor kappa B
• Glutaredoxin
• Lung
• Inhibitory kappa B kinase

The transcription factor nuclear factor kappa B (NF-kappa B) 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-kappa B activation. The mechanisms whereby expression of the Glrx1 gene is regulated remain unknown. Here we examined the role of NF-kappa B in regulating activation of Glrx1. Transgenic mice that express a doxycycline-inducible constitutively active version of inhibitory kappa B kinase-beta (CA-IKK beta) demonstrate elevated expression of Grx1. Transient transfection of CA-IKK beta also resulted in significant induction of Grx1. A 2-kb region of the Glrx1 promoter that contains two putative NF-kappa B binding sites was activated by CA-IKK beta, 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 IKK beta Overexpression of Grx1 decreased S-glutathionylation of IKK beta, prolonged NF-kappa B activation, and increased levels of proinflammatory mediators. Collectively, this study demonstrates that the Glrx1 gene is positively regulated by NF-kappa B and suggests a feed-forward mechanism to promote NF-kappa B signaling by decreasing S-glutathionylation.

• 出版日期2011-9-15