Thioredoxin 80 (Trx80): a novel cytokine that triggers the innate- and adaptive-immunity

Specific Goals
I. Investigate the molecular pathways by which Trx80 activates human monocytes to become effectors of the innate- and adaptive-immunity
II. Characterize the molecular mechanisms by which Trx80 regulate the immune response

Previous Results
Our studies demonstrate that Trx80 induce differentiation of human CD14+ monocytes into a novel cell type, which we have designated as Trx80-activated-monocytes (TAMs). TAMs have elevated expression of CD14, CD40, CD54 and CD86, and induce production of IL-12 by CD40+ monocytes in the presence of T cells. TAMs resemble immature dendritic cells (iDCs) generated in the presence of GM-CSF and IL-4 in that both these cell populations exhibit increased proportions of CD1a+ and mannose receptor (MR)+ cells. However, in contrast to iDC, TAMs express high proportion of CD14. Functional assays revealed that, in comparison to iDCs, TAMs i) exhibit a higher pinocytic capacity; and ii) release significantly higher amounts of the pro-inflammatory cytokines TNFa, IL-1b and IL-6 and of the anti-inflammatory cytokine IL-10. Indeed, Trx80 appears to be the first endogenous substance shown to have the capacity on its own to induce IL-10 production by monocytes.

Our findings shed new light on the functions of Trx80 in connection with both the inflammatory process and defenses against infectious microbes. We have proposed that Trx80 is an early signal in response to danger, and that TAMs are key effectors in triggering the innate and adaptive immune responses. Our results strongly suggest that Trx80 plays a major role in the innate immunity (by induction of TAMs and activation of NK cells), in the adaptive immunity (by induction of Th1 lymphocytes) and in the regulation of the immune response (by production of IL-10 and the induction of Tr cells). Further studies are essential to clarify how these processes are initiated and understand the molecular events that control these three different immune responses. Detailed knowledge of the molecular mechanisms by which Trx80 induces the different immune responses will be helpful: i) to induce anti-tumor responses; ii) in the defense against microbial infections, some of which are strongly associated with tumor progression; iii) to prevent or reduce undesirable chronic Th1 responses; iv) and possibly to elicit Tr cells for the induction of tolerance in transplanted individuals.

References
1. Pekkari, K., J. Avila-Carino, A. Bengtsson, R. Gurunath, A. Scheynius, and A. Holmgren. Truncated thioredoxin (Trx80) induces production of interleukin-12 and enhances CD14 expression in human monocytes. Blood 97:3184-90, 2001

2. Pekkari, K., J. Avila-Carino, R. Gurunath, A. Bengtsson, A. Scheynius, and A. Holmgren. Truncated thioredoxin (Trx80) exerts unique mitogenic cytokine effects via a mechanism independent of thiol oxido-reductase activity. FEBS Lett 539:143-8, 2003

3. Pekkari, K., M. T. Goodarzi, A. Scheynius, A. Holmgren, and J. Avila-Carino. Truncated thioredoxin (Trx80) induces differentiation of human CD14+ monocytes into a novel cell type (TAMs) via activation of the MAP kinases p38, ERK, and JNK. Blood 105:1598-605, 2005