Inflammation redox-sensitive transcription factors

Moreover GSH concentration indirectly controls a host of redox-sensitive transcription factors such as NF-kB and AP-1, modulates the genes for pro-inflammatory mediators as well as protective antioxidant genes such as y-GCS, Mn-superoxide dismutase, and heme oxygenase-1. Also TNF-a, p38 MAP kinase activation and p38 MAP kinase-mediated RANTES (regulated upon activation, normal T-cells expressed and secreted ) production is redox regulated [24]. The role of RANTES in the inflammatory and allergic response has been recently elucidated [25], indicating a role of intracellular GSH also in this particular field of inflammation. 

Nuclear factor kappa-B (NFkB), a redox-sensitive transcription factor regulating a battery of inflammatory genes, has been indicated to play a role in the development of numerous pathological states [189]. Activation of NFkB induces gene programs leading to transcription of factors that promote inflammation, such as leukocyte adhesion molecules, cytokines and chemokines [181]. 

The overall effects of Hey on vascular reactive oxygen species (ROS) generation adversely modulate vascular redox state and activate critical redox-sensitive transcriptional factors such as nuclear-factor kappa B or activator protein-1, which leads to a vicious cycle of inflammation - oxidative stress -endothelial dysfunction favouring vascular disease development. 

Redox sensitive transcriptional factors. Important intracellular pathways that control the expression of multiple genes. Their activation status is modulated by changes in intracellular redox state. Such transcriptional factors are the nuclear factor kappa-b or activating protein-1 that, at the level of the vascular wall, regulate the expression of proinflammatory genes and orchestrate vascular inflammation. 

The redox sensitive transcription factor NF-kB is responsible for mediating a number of stress responses, most notably inflammation and cell survival [508]. Extracellular and intracellular stimuli transmit their signals to the NF-kB/IkB complex via IkB kinases (IKKs), which phosphorylate IkB to mark it for degradation. NF-kB can then translocate to the nucleus and activate or repress genes involved in cell stress, survival, death, and differentiation. 

In vitro and animal studies clearly point to a central role of several distinct but interconnected redox-sensitive pathways in the pathogenesis of inflammation [47]. It has been hypothesized that oxidative stress occurs as a result of the depletion of the cellular content of reduced glutathione. A sublethal oxidative stress can activate redox-sensitive kinase cascades and transcription factors, NF-kB and AP-1, with resulting increases in the expression of factors associated with an inflammatory response and cellular proliferation. Evidence has been collected suggesting that oxidative stress and the ensuing modification of the cellular redox status may be associated with the induction of cell death either via stimulation of apoptosis and/or necrosis. It is well known that cell death is a common feature of the inflammatory process [48]. 

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