Identification of human thioredoxin as a novel IFN-gamma-induced factor: Mechanism of induction and its role in cytokine production

Background: IFN-gamma is a multifunctional peptide with a potent immune defense function which is also known as a prototypic Th1 cytokine. While screening for genes differentially expressed by Th1 and Th2 cytokines, human thioredoxin was identified as a novel target gene induced by IFN-gamma. The mechanism by which thioredoxin is induced by IFN-gamma and the signaling pathways involved in its induction were analyzed. In addition, the effects of thioredoxin on immune cell survival and cytokine production were examined by thioredoxin over-expression and recombinant thioredoxin treatment. Results: Human thioredoxin was selectively induced by IFN-gamma in monocytic and T cell lines. In monocytic cells, the induction of thioredoxin gene expression by IFN-gamma was dose-dependent, and both the mRNA and protein levels were increased by 2 similar to 3 fold within 4 to 24 h hours of IFN-gamma treatment. The thioredoxin induction by IFN-gamma was insensitive to cycloheximide treatment, suggesting that it is a primary response gene induced by IFN-gamma. Subsequent analysis of the signaling pathways indicated that the Jak/Stat, Akt, and Erk pathways play a role in IFN-gamma signaling that leads to thioredoxin gene expression. Thioredoxin was induced by oxidative or radiation stresses, and it protected the immune cells from apoptosis by reducing the levels of reactive oxygen species. Furthermore, thioredoxin modulated the oxidant-induced cytokine balance toward Th1 by counter-regulating the production of IL-4 and IFN-gamma in T cells. Conclusion: These data suggest that thioredoxin is an IFN-gamma-induced factor that may play a role in developing Th1 immunity and in the maintenance of immune homeostasis upon infection, radiation, and oxidative stress.