Thioredoxin reductase, a redox-active selenoprotein, is secreted by normaland neoplastic cells: Presence in human plasmal

Thioredoxin (Trx) and Trx reductase (TrxR) are redox-active proteins that p articipate in multiple cellular events, including growth promotion, apoptos is, and cytoprotection. Studies on overexpression of Trx and TrxR in human cancers have indicated a role of these proteins in tumor development. In th is study, we analyzed the expression of TrxR in peripheral blood cells, tum or-transformed Leukemia, and melanoma cells and found, in addition to abund ant plasma membrane localization, that TrxR was released from these cells. Secretory cells were observed at the single cell level using a sensitive en zyme-linked immunospot assay. The release was inducible, and physiological stimulation of human monocytes by IFN-gamma, lipopolysaccharide, and interl eukin lot significantly increased the number of TrxR-secreting cells (P = 0 .004). Secretion of TrxR followed the classical Golgi pathway, and it was c onfirmed by metabolic labeling using [S-35]methionine and [S-35]cysteine. T rxR was also detected for the first time in fresh healthy blood donor plasm a (n = 21; median concentration, 18.0 ng/ml), with biological activity as d etermined by insulin reduction assay. These results highlight the role of extracellular Trx and TrxR during infla mmation and tumor progression. Released Trx, with its active site motif con taining amino acids Cys-X-X-Cys, was recently shown to have chemoattractant properties beside its previously described antioxidant and cocytokine acti vities. Regeneration of oxidized Trx requires available TrxR outside the ce ll, the presence and induction of which is described in this paper for norm al and transformed cells.