Thioredoxin-mediated denitrosylation regulates cytokine-induced NF-{kappa}B activation [Immunology]

December 12th, 2013 by Kelleher, Z. T., Sha, Y., Foster, M. W., Foster, W. M., Forrester, M. T., Marshall, H. E.

S-nitrosylation of nuclear factor kappa B (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.