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Förslaget inkom 2005-08-28

Thioredoxin 80 (Trx80): A trigger of the Innate- and Adaptive-immunity

Thioredoxin (Trx) is a major intracellular protein-disulfide reductase and hereby regulates a wide variety of enzymes, receptors and transcription factors. A truncated form of thioredoxin (Trx80) is present in the plasma and recombinant Trx80 evokes proliferation of both normal human peripheral blood mononuclear cells (PBMC) and purified human monocytes. We have found that Trx80 induce differentiation of human CD14+ monocytes into a cell type not described previously, 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. We propose that Trx80 is an early signal in response to danger, and that TAMs may play a major role in triggering innate immune responses.

General Aim
Study the mechanisms by which Trx80 triggers the innate- and the adaptive-immunity

Specific Aims
I. Investigate the molecular pathways by which Trx80 activates human monocytes to become effectors of the innate immunity
II. Study the events by which Trx80 induces differentiation of human monocytes into specialized cells that promote the induction of a T helper (Th)1 response
III. Analyze the mechanisms by which Trx80 regulate the immune response

1. Pekkari K. et al. Truncated thioredoxin (Trx80) induces interleukin 12 production and enhances CD14 expression in human monocytes. Blood. 97:3184-3190, 2001
2. Pekkari K et al. 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 et al. 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. In press.


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