title: Thioredoxin-mediated denitrosylation regulates cytokine-induced nuclear factor κB (NF-κB) activation.
abstract: S-nitrosylation of nuclear factor κB (NF-κB) on the p65 subunit of the p50/p65 heterodimer inhibits NF-κB DNA binding activity. We have recently shown that p65 is constitutively S-nitrosylated in the lung and that LPS-induced injury elicits a decrease in SNO-p65 levels concomitant with NF-κB activation in the respiratory epithelium and initiation of the inflammatory response. Here, we demonstrate that TNFα-mediated activation of NF-κB in the respiratory epithelium similarly induces p65 denitrosylation. This process is mediated by the denitrosylase thioredoxin (Trx), which becomes activated upon cytokine-induced degradation of thioredoxin-interacting protein (Txnip). Similarly, inhibition of Trx activity in the lung attenuates LPS-induced SNO-p65 denitrosylation, NF-κB activation, and airway inflammation, supporting a pathophysiological role for this mechanism in lung injury. These data thus link stimulus-coupled activation of NF-κB to a specific, protein-targeted denitrosylation mechanism and further highlight the importance of S-nitrosylation in the regulation of the immune response.
authors: From the Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University Medical Center, Durham, North Carolina 27710 and.
authors: Zachary T
authors: ZT
authors: Kelleher
authors: Yonggang
authors: Y
authors: Sha
authors: Matthew W
authors: MW
authors: Foster
authors: W Michael
authors: WM
authors: Foster
authors: Michael T
authors: MT
authors: Forrester
authors: Harvey E
authors: HE
authors: Marshall
mesh_terms: D000230:Adenocarcinoma; D000818:Animals; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D055370:Lung Injury / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008175:Lung Neoplasms; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D026361:Reactive Nitrogen Species / Q000378:metabolism; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000276:immunology*; D013879:Thioredoxins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism*
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D052002:NF-kappa B p50 Subunit; D026361:Reactive Nitrogen Species; C491203:TXN protein, human; D051996:Transcription Factor RelA; C515559:Txn1 protein, mouse; D009569:Nitric Oxide; D013879:Thioredoxins
keywords: Lung Injury; NF-κB; Nitric Oxide; S-nitrosylation; Thioredoxin