Glutathione S-transferase pi modulates NF-κB activation and pro-inflammatory responses in lung epithelial cells. Redox Biol 2016 Aug;8:375-82
Date
04/09/2016Pubmed ID
27058114Pubmed Central ID
PMC4827796DOI
10.1016/j.redox.2016.03.005Scopus ID
2-s2.0-84962160052 (requires institutional sign-in at Scopus site) 71 CitationsAbstract
Nuclear Factor kappa B (NF-κB) is a transcription factor family critical in the activation of pro- inflammatory responses. The NF-κB pathway is regulated by oxidant-induced post-translational modifications. Protein S-glutathionylation, or the conjugation of the antioxidant molecule, glutathione to reactive cysteines inhibits the activity of inhibitory kappa B kinase beta (IKKβ), among other NF-κB proteins. Glutathione S-transferase Pi (GSTP) is an enzyme that has been shown to catalyze protein S-glutathionylation (PSSG) under conditions of oxidative stress. The objective of the present study was to determine whether GSTP regulates NF-κB signaling, S-glutathionylation of IKK, and subsequent pro-inflammatory signaling. We demonstrated that, in unstimulated cells, GSTP associated with the inhibitor of NF-κB, IκBα. However, exposure to LPS resulted in a rapid loss of association between IκBα and GSTP, and instead led to a protracted association between IKKβ and GSTP. LPS exposure also led to increases in the S-glutathionylation of IKKβ. SiRNA-mediated knockdown of GSTP decreased IKKβ-SSG, and enhanced NF-κB nuclear translocation, transcriptional activity, and pro-inflammatory cytokine production in response to lipopolysaccharide (LPS). TLK117, an isotype-selective inhibitor of GSTP, also enhanced LPS-induced NF-κB transcriptional activity and pro-inflammatory cytokine production, suggesting that the catalytic activity of GSTP is important in repressing NF-κB activation. Expression of both wild-type and catalytically-inactive Y7F mutant GSTP significantly attenuated LPS- or IKKβ-induced production of GM-CSF. These studies indicate a complex role for GSTP in modulating NF-κB, which may involve S-glutathionylation of IKK proteins, and interaction with NF-κB family members. Our findings suggest that targeting GSTP is a potential avenue for regulating the activity of this prominent pro-inflammatory and immunomodulatory transcription factor.
Author List
Jones JT, Qian X, van der Velden JL, Chia SB, McMillan DH, Flemer S, Hoffman SM, Lahue KG, Schneider RW, Nolin JD, Anathy V, van der Vliet A, Townsend DM, Tew KD, Janssen-Heininger YMAuthor
Test W. User test user title in the Anesthesiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAsthma
Cell Line
Disease Models, Animal
Epithelial Cells
Glutaredoxins
Glutathione S-Transferase pi
Humans
I-kappa B Kinase
Inflammation
Lipopolysaccharides
Lung
Mice
NF-kappa B
Oxidative Stress
Protein Processing, Post-Translational
Signal Transduction
