A rchivum Immunologiae et Therapiae Experimentalis, 2001, 4 9, 285–292 P L ISSN 0004-069X Review Redox Control of Cellular Function by Thioredoxin; a New Therapeutic Direction in Host Defence YUMIKO NISHINAKA, HAJIME NAKAMURA, HIROSHI MASUTANI and JU NJI YO DOI* Y. Nishinaka et al.: Redox Control of Cellular Function Department of Biological Responses, Institute for Virus Research, Kyoto University, 53 Shog oin-Kawaharacho, Sakyo, Kyoto 606-8507, Japan A bstract. Compelling evidence has suggested that oxidative stress mediates various cellular respon ses, and c ontrol of reduction/oxidation (redox) is important in maintaining the homeostasis of an organism. The thioredoxin (TRX) system, as well as the glutathione system, is one of the key systems in controlling cellular redox status. T RX is a small ubiquitous protein with the redox-active site sequence -Cys-Gly-Pro-Cys-. It has been demon- strated to be a multifunctional protein, which has regulatory roles in cellular signaling and gene transcription in a ddition to cytoprotective activities through the quenching of reactive oxygen species. Va rious oxidative stimuli, such as UV irradiation, cytokines and some chemicals, promptly induce the expression of TRX. Overexpression o f TRX correlates with a wide variety of oxidative stress conditions and, in some cases, TRX has shown promising e ffects for clinical use, for instance in the attenuation of tissue injury in ischemia reperfusion models. The m odulation of TRX functions in association with other redox-regulatory molecules should give us a new thera- p eutic strategy in the treatment of oxidative stress-mediated disorders and diseases. Key words: redox regulation; thioredoxin; reactive oxygen species; therapy. I ntroduction O xygen is indispensable for the maintenance of life i n aerobic organisms, from bacteria to mammals. Reac- t ive oxygen species (ROS) are naturally generated from o xygen during respiration for energy metabolism, or in r esponse to various stimuli, such as UV irradiation, X-ray, inflammatory cytokines and chemical carcino- g ens. ROS include superoxide, singlet oxygen, H 2 O 2 a nd the highly reactive hydroxyl radical. ROS can alter o r disrupt the balance of redox status in cells, which c auses various dysfunctions and diseases 3 6, 44 . Recently, R OS have been shown to act as signal-transduction c omponents in regulating cellular responses 1, 44 . Ac- c ordingly, homeostatic control of ROS is thought to be o ne of the key determinants in maintaining cell growth p athways, which include proliferation, apoptosis and senescence. Living cells have evolved several systems t o maintain intracellular redox status by scavenging ROS. These systems include the glutathione (GSH) 10 a nd the thioredoxin (TRX) systems 13 . Oxidative condi- t ions may produce conformational changes and d imer/multimer formation of redox sensitive proteins, r esulting in the functional modulation of those proteins. The GSH and TRX systems reverse the disulfide for- mation of proteins. Change of the intracellular GSH l evel is highly sensitive to oxidative stress. Expression o f TRX is also promptly induced by a variety of oxi- * Correspondence to: Junji Yodoi, M.D. Ph.D., Department of Biological Responses, Institute for Virus Research, Kyoto University, 5 3 Shogoin-Kawaharacho, Sakyo, Kyoto 606-8507, Japan, tel.: +81 75 751 4024, fax: +81 75 761 5766, e-mail: yodoi@virus.kyoto-u.ac.jp