Tumor-secreted lactic acid promotes IL-23/IL-17 proinflammatory pathway.
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-gamma 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.
Shime
Hiroaki
H
Department of Molecular Genetics, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
Yabu
Masahiko
M
Akazawa
Takashi
T
Kodama
Ken
K
Matsumoto
Misako
M
Seya
Tsukasa
T
Inoue
Norimitsu
N
D000818:Animals; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D015972:Gene Expression Regulation, Neoplastic; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism*; D053759:Interleukin-23 / Q000276:immunology / Q000378:metabolism*; D053760:Interleukin-23 Subunit p19 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism*; D008024:Ligands; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*; D014158:Transcription, Genetic
D017077:Culture Media, Conditioned; D020381:Interleukin-17; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D008024:Ligands; D051193:Toll-Like Receptors; D019344:Lactic Acid; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor