Redox Regulation of Cellular Activation

Abstract

Growing evidence has indicated that cellular reduction/oxidation (redox) status regulates various aspects of cellular function. Oxidative stress can elicit positive responses such as cellular proliferation or activation, as well as negative responses such as growth inhibition or cell death. Cellular redox status is maintained by intracellular redox-regulating molecules, including thioredoxin (TRX). TRX is a small multifunctional protein that has a redox-active disulfide/dithiol within the conserved active site sequence: Cys-Gly-Pro-Cys. Adult T cell leukemia-derived factor (ADF), which we originally defined as an IL-2 receptor alpha-chain/Tac inducer produced by human T cell lymphotrophic virus-I (HTLV-I)-transformed T cells, has been identified as human TRX. TRX/ADF is a stress-inducible protein secreted from cells. TRX/ADF has both intracellular and extracellular functions as one of the key regulators of signaling in the cellular responses against various stresses. Extracellularly, TRX/ADF shows a cytoprotective activity against oxidative stress-induced apoptosis and a growth-promoting effect as an autocrine growth factor. Intracellularly, TRX/ADF is involved in the regulation of protein-protein or protein-nucleic acid interactions through the reduction/oxidation of protein cysteine residues. For example, TRX/ADF translocates from the cytosol into the nucleus by a variety of cellular stresses, to regulate the expression of various genes through the redox factor-1 (Ref-1)/APEX. Further studies to clarify the regulatory roles of TRX/ADF and its target molecules may elucidate the intracellular signaling pathways in the responses against various stresses. The concept of "redox regulation" is emerging as an understanding of the novel mechanisms in the pathogenesis of several disorders, including viral infections, immunodeficiency, malignant transformation, and degenerative disease.

Increased plasma thioredoxin in patients with acute myocardial infarction

“…6 Although the precise mechanism of thioredoxin secretion is still not clarified, plasma levels of human thioredoxin are the response against oxidative stress. 7 There is a possibility that plasma thioredoxin levels were elevated by the inflammatory response against the oxidative stress in patients with AMI in the present study.…”

Thioredoxin suppresses airway inflammation independently of systemic Th1/Th2 immune modulation

“…TRX is a 12 kDa protein with a highly conserved redox-active dithiol/disulfide active site sequence, Cys 32 -Gly-Pro-Cys 35 , which, together with GSH constitutes the major redox-regulating molecules that maintain cellular redox balance [16,17]. Several studies have demonstrated protective effect of TRX in diseases associated with increased oxidative stress such as post-ischaemic reperfusion injury, adriamycin-induced cardiotoxicity and diabetic nephropathy [18][19][20][21].…”

Transgenic mice overproducing human thioredoxin-1, an antioxidative and anti-apoptotic protein, prevents diabetic embryopathy

“…TRX has been shown to protect cells from oxidative stress and apoptosis [15][16][17]. Several studies have shown that TRX is induced by various types of stress, such as viral infection, ischaemic insult, ultraviolet light, X-ray irradiation and H 2 O 2 [18]. TRX acts as a scavenger of ROS and can repair proteins oxidised by ROS [13,18].…”

“…Several studies have shown that TRX is induced by various types of stress, such as viral infection, ischaemic insult, ultraviolet light, X-ray irradiation and H 2 O 2 [18]. TRX acts as a scavenger of ROS and can repair proteins oxidised by ROS [13,18]. In-vitro studies have demonstrated that TRX has a protective effect against the cytotoxicity of ROS [18].…”