Induction of IFN-gamma gene expression by thioredoxin: positive feed-back regulation of Th1 response by thioredoxin and IFN-gamma.

T cell differentiation, which leads to the generation of Th cells with a characteristic cytokine expression pattern, is regulated by diverse factors. In addition to the cytokine environment, the cellular redox status often serves as an important factor in survival and differentiation of Th cells. Thioredoxin, an intracellular redox sensor protein, has been suggested in the induction of Th1 response through the production of IL-12 by monocytes. Here we report that thioredoxin expression is up-regulated by IFN-gamma and other Th1 type cytokines in human primary immune cells, and that the overexpression of thioredoxin resulted in a specific increase in the mRNA level and promoter activity of IFN-gamma in mitogen-stimulated Jurkat T cells. Using the active site mutant (C32S/C35S) of thioredoxin, we demonstrate that such IFN-gamma-inducing capacity of thioredoxin is dependent on the redox-sensing activity of thioredoxin and involves the activation of transcription factors such as NF-kappaB and Stat1. Together, the results of the present study suggest that thioredoxin is a direct stimulator of IFN-gamma gene expression in human T cells and that there is a positive feed-back circuit by IFN-gamma and thioredoxin in the regulation of Th1 immune response.