title: Adult T cell leukemia (ATL)-derived factor/human thioredoxin prevents apoptosis of lymphoid cells induced by L-cystine and glutathione depletion: possible involvement of thiol-mediated redox regulation in apoptosis caused by pro-oxidant state.
abstract: Thiol compounds, such as L-cysteine and glutathione (GSH), play crucial roles in the regulation of lymphocyte proliferation. In this study, we analyzed the effect of L-cystine and GSH depletion on lymphocyte survival and investigated the regulatory roles of adult T cell leukemia (ATL)-derived factor (ADF)/human thioredoxin (hTRX) in relation to these low m.w. thiols. MT-1, MT-2, and Jurkat cells underwent apoptosis when cultured in the L-cystine- and GSH-free medium within 18 to 24 h. Dichlorofluorescin oxidation assay indicated that the apoptosis in MT-1 and MT-2 cells was preceded by an increase in the level of intracellular hydrogen peroxide (H2O2). The addition of catalase and recombinant ADF/hTRX (rADF) partially blocked the apoptosis in a dose-dependent manner. rADF has been also shown to enhance the internalization of L-cystine into MT-2 cells in a dose-dependent manner, whereas oxidized rADF or mutated rADF that has no insulin-reducing activity failed to do so. Furthermore, culture in the L-cystine- and GSH-free medium lowered the cellular GSH content of PHA blasts, which was restored dose-dependently by rADF. These data suggest that the inability to neutralize oxidative stress results in the apoptosis of lymphoid cells under L-cystine- and GSH-depleted conditions. The protective effects of rADF may be explained by direct scavenging action on H2O2 (catalase-like activity) or by indirect neutralizing effects on the pro-oxidant status through enhancing the L-cystine internalization and elevating the intracellular GSH content.
authors.affiliation: Department of Biological Responses, Kyoto University, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Iwata
authors.forename: T
authors.initials: T
authors.lastname: Hori
authors.forename: N
authors.initials: N
authors.lastname: Sato
authors.forename: K
authors.initials: K
authors.lastname: Hirota
authors.forename: T
authors.initials: T
authors.lastname: Sasada
authors.forename: A
authors.initials: A
authors.lastname: Mitsui
authors.forename: T
authors.initials: T
authors.lastname: Hirakawa
authors.forename: J
authors.initials: J
authors.lastname: Yodoi
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002374:Catalase / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003470:Culture Media; D003553:Cystine / Q000172:deficiency / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics / Q000494:pharmacology*; D005978:Glutathione / Q000172:deficiency / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D008970:Molecular Weight; D009363:Neoplasm Proteins / Q000235:genetics / Q000494:pharmacology*; D016877:Oxidants / Q000494:pharmacology*; D010084:Oxidation-Reduction; D011994:Recombinant Proteins / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000378:metabolism / Q000494:pharmacology*; D013879:Thioredoxins / Q000494:pharmacology*
chemical_list: D003470:Culture Media; D016207:Cytokines; D009363:Neoplasm Proteins; D016877:Oxidants; D011994:Recombinant Proteins; D013438:Sulfhydryl Compounds; C055533:adult T cell leukemia-derived factor; D003553:Cystine; D013879:Thioredoxins; D006861:Hydrogen Peroxide; D002374:Catalase; D005978:Glutathione