Involvement of Reactive Oxygen Species in Toll-Like Receptor 4-Dependent Activation of NF-κB

Abstract

Although oxidative stress has been thought to play a general role in the activation of NF-κB, the involvement of reactive oxygen species (ROS) in facilitating nuclear translocation of NF-κB in neutrophils has not been described. In addition, the mechanisms by which ROS modulate the transcriptional activity of NF-κB in response to Toll-like receptor 4 (TLR4)-dependent signaling are not well characterized. To examine these issues, oxidant-dependent signaling events downstream of TLR4 were investigated in neutrophils stimulated with LPS. Pretreatment of neutrophils with the antioxidants N-acetylcysteine or α-tocopherol prevented LPS-induced nuclear translocation of NF-κB. Antioxidant treatment of LPS-stimulated neutrophils also inhibited the production of proinflammatory cytokines (TNF-α, macrophage inflammatory protein-2, and IL-1β), as well as activation of the kinases IκB kinase α, IκB kinase β, p38, Akt, and extracellular receptor-activated kinases 1 and 2. The decrease in cytoplasmic levels of IκBα produced by exposure of neutrophils to LPS was prevented by N-acetylcysteine or α-tocopherol. Activation of IL-1R-associated kinase-1 (IRAK-1) and IRAK-4 in response to LPS stimulation was inhibited by antioxidants. These results demonstrate that proximal events in TLR4 signaling, at or antecedent to IRAK-1 and IRAK-4 activation, are oxidant dependent and indicate that ROS can modulate NF-κB-dependent transcription through their involvement in early TLR4-mediated cellular responses.

Reactive oxygen species–independent activation of the IL-1β inflammasome in cells from patients with chronic granulomatous disease

“…These effects of DPI were exerted at the level of transcription, with repression of mRNA for both TNF-α and IL-1β, whereas the active caspase-1 p35 fragment was normally present. Our data demonstrating that the anti-inflammatory effects of DPI on IL-1β production are exerted at the transcriptional level are in line with the large body of literature reporting that ROS induce NF-κB activation (12,23,24). In addition, the clear inhibition of cytokine stimulation by DPI in cells of CGD patients, a system in which ROS production is defective, clearly demonstrates that the effects of DPI on cytokine production are largely independent of NADPH oxydase generation of ROS.…”

Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

“…[59][60][61] In fact, it has been widely reported that NF-kB is activated by H 2 O 2 and other oxidants. [62][63][64][65][66] In the present study, we demonstrated that H 2 O 2 mediates its action through the ALK5/ Smad3/NF-kB intracellular pathway. These findings suggest possibly that the NF-kB transcription factor is involved in the modification of protein expression that is induced by oxidative stress.…”

“…Taken together, the results shown here provide evidence that oxidative stress is a crucial factor in inducing the conversion of ECs into myofibroblasts through a TGF-bdependent mechanism that produces changes in EC protein [62][63][64][65][66] This gene expression could be involved in the H 2 O 2 -induced conversion of ECs into myofibroblasts because inhibition of NF-kB using IKK-16 inhibited the conversion. (iii) Our results showed that H 2 O 2 induces the phosphorylation of p38MAPK.…”

Sepsis, mitochondrial failure and multiple organ dysfunction

“…RNS are also involved in the regulation of blood pressure and vascular tone [12], the activation of NFκβ by TLR-4 receptors [17], the release of inammatory cytokines and the expression of adhesion molecules [18]. Finally, they are inducers of the antioxidant response that is pivotal for maintaining redox balance.…”

“…ROS can activate the nuclear factor κβ (NFκβ), induce apoptosis, increase the expression of transcription factors and prolong in ammatory processes [17]. H2O2 is an ROS that easily di uses through the cell membranes.…”