| RRC ID |
6567
|
| 著者 |
Shime H, Yabu M, Akazawa T, Kodama K, Matsumoto M, Seya T, Inoue N.
|
| タイトル |
Tumor-secreted lactic acid promotes IL-23/IL-17 proinflammatory pathway.
|
| ジャーナル |
J Immunol
|
| 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-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.
|
| 巻・号 |
180(11)
|
| ページ |
7175-83
|
| 公開日 |
2008-6-1
|
| DOI |
10.4049/jimmunol.180.11.7175
|
| PII |
180/11/7175
|
| PMID |
18490716
|
| MeSH |
Animals
Cell Line, Tumor
Culture Media, Conditioned
Gene Expression Regulation, Neoplastic
Granulocyte-Macrophage Colony-Stimulating Factor / immunology
Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
Humans
Hydrogen-Ion Concentration
Interferon-gamma / immunology
Interferon-gamma / metabolism
Interleukin-17 / immunology
Interleukin-17 / metabolism*
Interleukin-23 / immunology
Interleukin-23 / metabolism*
Interleukin-23 Subunit p19 / genetics
Interleukin-23 Subunit p19 / immunology
Interleukin-23 Subunit p19 / metabolism*
Lactic Acid / metabolism*
Ligands
Macrophages / immunology
Macrophages / metabolism
Melanoma, Experimental / immunology
Mice
Mice, Inbred C57BL
Monocytes / immunology
Monocytes / metabolism
Promoter Regions, Genetic
Toll-Like Receptors / immunology
Toll-Like Receptors / metabolism*
Transcription, Genetic
|
| IF |
4.886
|
| 引用数 |
137
|
|
WOS 分野
|
IMMUNOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
J774.1(RCB0434) |
