Tumor-secreted lactic acid promotes IL-23/IL-17 proinflammatory pathway

H Shime, M Yabu, T Akazawa, K Kodama… - The Journal of …, 2008 - journals.aai.org
H Shime, M Yabu, T Akazawa, K Kodama, M Matsumoto, T Seya, N Inoue
The Journal of Immunology, 2008journals.aai.org
IL-23 is a proinflammatory cytokine consisting of a p19 subunit and a p40 subunit that is
shared with IL-12. IL-23 is overexpressed in and around tumor tissues, where it induces
local inflammation and promotes tumor development. Many tumor cells produce large
amounts of lactic acid by altering their glucose metabolism. In this study, we show that lactic
acid secreted by tumor cells enhances the transcription of IL-23p19 and IL-23 production in
monocytes/macrophages and in tumor-infiltrating immune cells that are stimulated with …
Abstract
IL-23 is a proinflammatory cytokine consisting of a p19 subunit and a p40 subunit that is shared with IL-12. IL-23 is overexpressed in and around tumor tissues, where it induces local inflammation and promotes tumor development. Many tumor cells produce large amounts of lactic acid by altering their glucose metabolism. In this study, we show that lactic acid secreted by tumor cells enhances the transcription of IL-23p19 and IL-23 production in monocytes/macrophages and in tumor-infiltrating immune cells that are stimulated with TLR2 and 4 ligands. DNA elements responsible for this enhancing activity of lactic acid were detected in a 2.7-kb 5′-flanking region of the human IL-23p19 gene. The effect of lactic acid was strictly regulated by extracellular pH. Furthermore, by inducing IL-23 overproduction, lactic acid facilitated the Ag-dependent secretion of proinflammatory cytokine IL-17 but not IFN-γ by TLR ligand-stimulated mouse splenocytes. Interestingly, this effect was observed even in the absence of TLR ligand stimulation. These results suggest that rather than just being a terminal metabolite, lactic acid is a proinflammatory mediator that is secreted by tumor cells to activate the IL-23/IL-17 proinflammatory pathway but not the Th1 pathway. Targeting the lactic acid-induced proinflammatory response may be a useful approach for treating cancer.
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