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.