Abstract
Several serine proteases have been linked to autoimmune disorders and tumour initiation although the mechanisms are not fully understood. Activation of the kynurenine pathway enzyme indoleamine-2,3-dioxygenase (IDO1) modulates cellular activity in the brain, tolerogenesis in the immune system and is a major checkpoint in cancer development. We now report that IDO1 mRNA and IDO1 protein expression (generating kynurenine) are induced in human monocyte-derived macrophages by several chymotryptic serine proteases with direct links to tumorigenesis, including Prostate Specific Antigen (PSA), CD26 (Dipeptidyl-peptidase-4, CD26/DPP-4), High Temperature Requirement protein-A (HtrA), and the bacterial virulence factor subtilisin. These proteases also induce expression of the pro-inflammatory cytokine genes IL1B and IL6. Other serine proteases tested: bacterial glu-C endopeptidase and mammalian Pro-protein Convertase Subtilase-Kexin-3 (PCSK3, furin), urokinase plasminogen activator (uPA), cathepsin G or neutrophil elastase, did not induce IDO1, indicating that the reported effects are not a general property of all serine proteases. The results represent a novel mechanism of activating immunosuppressive IDO1 and inducing kynurenine generation which, together with the production of inflammatory cytokines, would contribute to tumour initiation and progression, providing a new target for drug development. In addition, the proteasomal S20 serine protease inhibitor carfilzomib, used in the treatment of myeloma, prevented the induction of IDO1 and cytokine gene expression, potentially contributing to its clinical anti-cancer activity.
Highlights
The kynurenine pathway, especially the initiating enzyme indoleamine-2,3-dioxygenase-1 (IDO1), is induced in antigenpresenting cells by pro-inflammatory mediators such as interferon-g (IFN-g) and bacterial lipopolysaccharides (LPS) [1–3]
When human monocyte-derived macrophages were exposed for 24 h to LPS (10 ng/mL) the expression of IDO1 was increased compared with unstimulated cells (Figure 1)
To assess whether the induction of IDO1 was translated into protein expression, Western blots were performed on macrophage extracts
Summary
The kynurenine pathway, especially the initiating enzyme indoleamine-2,3-dioxygenase-1 (IDO1), is induced in antigenpresenting cells by pro-inflammatory mediators such as interferon-g (IFN-g) and bacterial lipopolysaccharides (LPS) [1–3]. The precise molecular mechanisms underlying these associations remain unclear in most cases a series of chymotryptic serine proteases down-regulate the tumour suppressor dependence receptors Deleted in Colorectal Cancer, neogenin and unco-ordinated-5 (unc5) [30], leading to a partial epithelialmesenchymal transition and increased cell migration [31, 32]. In view of these links between serine proteases, kynurenines, inflammation and tumour development, we have examined several proteases for possible interactions with the kynurenine pathway. The mammalian transmembrane T cell activator CD26, which exhibits dipeptidyl-peptidase-4 (DPP-4) serine protease activity and is expressed by many cell types, and Prostate Specific Antigen (PSA) were examined
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