| First Author | Nolin JD | Year | 2014 |
| Journal | Free Radic Biol Med | Volume | 73 |
| Pages | 143-53 | PubMed ID | 24816292 |
| Mgi Jnum | J:222008 | Mgi Id | MGI:5643845 |
| Doi | 10.1016/j.freeradbiomed.2014.04.028 | Citation | Nolin JD, et al. (2014) The glutaredoxin/S-glutathionylation axis regulates interleukin-17A-induced proinflammatory responses in lung epithelial cells in association with S-glutathionylation of nuclear factor kappaB family proteins. Free Radic Biol Med 73:143-53 |
| abstractText | Interleukin-17A (IL-17A) is a newly emerging player in the pathogenesis of chronic lung diseases that amplifies inflammatory responses and promotes tissue remodeling. Stimulation of lung epithelial cells with IL-17A leads to activation of the transcription factor nuclear factor kappaB (NF-kappaB), a key player in the orchestration of lung inflammation. We have previously demonstrated the importance of the redox-dependent posttranslational modification S-glutathionylation in limiting activation of NF-kappaB and downstream gene induction. Under physiological conditions, the enzyme glutaredoxin 1 (Grx1) acts to deglutathionylate NF-kappaB proteins, which restores functional activity. In this study, we sought to determine the impact of S-glutathionylation on IL-17A-induced NF-kappaB activation and expression of proinflammatory mediators. C10 mouse lung alveolar epithelial cells or primary mouse tracheal epithelial cells exposed to IL-17A show rapid activation of NF-kappaB and the induction of proinflammatory genes. Upon IL-17A exposure, sulfenic acid formation and S-glutathionylated proteins increased. Assessment of S-glutathionylation of NF-kappaB pathway components revealed S-glutathionylation of RelA (RelA-SSG) and inhibitory kappaB kinase alpha (IKKalpha-SSG) after stimulation with IL-17A. SiRNA-mediated ablation of Grx1 increased both RelA-SSG and IKKalpha-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 the NF-kappaB-regulated genes KC and CCL20 in response to IL-17A, but conversely increased the expression of IL-6. Last, siRNA-mediated ablation of IKKalpha 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 IKKalpha and RelA S-glutathionylation and the responsiveness of epithelial cells to IL-17A. |
