Thioredoxin is secreted from cells via a nonclassical pathway, since TRX does not possess signal sequence (36,37). Extracellular TRX has cytokine- or chemokine-like activity. Human TRX has growth-promoting effect on leukemic cells and hepa-tocellular carcinoma cells (7,38). Thioredoxin enhances migration of eosinophils (39) and shows the chemotactic activity on neutrophils, monocytes, and T lymphocytes (40,41). Because TRX does not increase intracellular Ca2+, the chemo-tactic activity of TRX seems to differ from that of known chemokines whose receptors are coupled with G proteins (40).

Recently, we reported that the release of TRX is augmented by hydrogen peroxide and suppressed by the addition of NAC or recombinant human TRX (rhTRX) extracellularly (42,43) (Fig. 2). We reported that fluorescence-labeled or his-tidine-tagged rhTRX enters the cells within 1-3 days (42), suggesting that cytoprotective effect of extracellular TRX may partly be due to scavenging ROS intracellularly after entering cells as well as extracellularly coupled with peroxir-edoxin IV (secretable type) (Figs. 2 and 3).

The serum or plasma level of TRX is regarded as a good marker of oxidative stress. The enzyme-linked immunosor-bent assay (ELISA) system using anti-TRX monoclonal

Figure 3 The suppressive effect of TRX on inflammation; TRX suppresses the activation, adhesion, and extravasation of neutrophils. LPS, lipopolysaccharide.

antibodies has been developed to measure the levels of TRX in serum/plasma or other body fluids (44). The serum/plasma levels of TRX in healthy persons are around 20-30 ng/mL. Elevation of serum/plasma TRX is reported in patients with HIV (43,44), hepatitis C virus infection (45), rheumatoid arthritis (46-48), heart failure (49,50), and surgical stress (51). The elevated levels of TRX seem to be correlated with the severity of the diseases, and the level can be a good indicator of the diagnosis or the therapy.

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