The glutaredoxin/S-glutathionylation axis regulates interleukin 17A-induced pro-inflammatory responses in lung epithelial cells in association with S-glutathionylation of Nuclear Factor kappa B family proteins.

In this study, we sought to determine the impacts of S-glutathionylation on IL-17A-induced NF-κB activation and expression of pro-inflammatory mediators. C10 mouse lung alveolar epithelial cells, or primary mouse tracheal epithelial cells exposed to IL-17A show rapid activation of NF-κB, and the induction of pro-inflammatory genes. Upon IL-17A exposure, sulfenic acid formation and S-glutathionylated proteins increased. Assessment of S-glutathionylation of NF-κB pathway components revealed S-glutathionylation of RelA (RelA-SSG) and inhibitory kappa B kinase alpha (IKKα-SSG) after stimulation with IL-17A. SiRNA-mediated ablation of Grx1 increased both RelA-SSG and IKKα-SSG and acutely increased nuclear content of RelA, and tended to decrease nuclear RelB. SiRNA mediated ablation or genetic ablation of Glrx1 decreased the expression of NF-κB regulated genes, KC and CCL20, in response to IL-17A, but conversely increased the expression of IL-6. Lastly, siRNA-mediated ablation of IKKα attenuated nuclear RelA and RelB content and decreased expression of KC and CCL20 in response to IL-17A. Together, these data demonstrate a critical role for the S-glutathionylation/Grx1 redox axis in regulating IKKα and RelA S-glutathionylation and the responsiveness of epithelial cells to IL-17A.
PMID: 24816292 [PubMed - as supplied by publisher]

Source: Free Radical Biology and Medicine - May 6, 2014 Category: Biology Authors: Nolin JD, Tully JE, Hoffman SM, Guala AS, van der Velden JL, Poynter ME, van der Vliet A, Anathy V, Janssen-Heininger YM Tags: Free Radic Biol Med Source Type: research