Document Detail

Tumor-secreted lactic acid promotes IL-23/IL-17 proinflammatory pathway.
MedLine Citation:
PMID:  18490716     Owner:  NLM     Status:  MEDLINE    
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.
Hiroaki Shime; Masahiko Yabu; Takashi Akazawa; Ken Kodama; Misako Matsumoto; Tsukasa Seya; Norimitsu Inoue
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  180     ISSN:  0022-1767     ISO Abbreviation:  J. Immunol.     Publication Date:  2008 Jun 
Date Detail:
Created Date:  2008-05-20     Completed Date:  2008-07-18     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  7175-83     Citation Subset:  AIM; IM    
Department of Molecular Genetics, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
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MeSH Terms
Cell Line, Tumor
Culture Media, Conditioned
Gene Expression Regulation, Neoplastic
Granulocyte-Macrophage Colony-Stimulating Factor / immunology,  metabolism
Hydrogen-Ion Concentration
Interferon-gamma / immunology,  metabolism
Interleukin-17 / immunology,  metabolism*
Interleukin-23 / immunology,  metabolism*
Interleukin-23 Subunit p19 / genetics,  immunology,  metabolism*
Lactic Acid / metabolism*
Macrophages / immunology,  metabolism
Melanoma, Experimental / immunology
Mice, Inbred C57BL
Monocytes / immunology,  metabolism
Promoter Regions, Genetic
Toll-Like Receptors / immunology,  metabolism*
Transcription, Genetic
Reg. No./Substance:
0/Culture Media, Conditioned; 0/Interleukin-17; 0/Interleukin-23; 0/Interleukin-23 Subunit p19; 0/Ligands; 0/Toll-Like Receptors; 50-21-5/Lactic Acid; 82115-62-6/Interferon-gamma; 83869-56-1/Granulocyte-Macrophage Colony-Stimulating Factor

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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