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Tumor-Secreted Lactic Acid Promotes IL-23/IL-17 Proinflammatory Pathway¹

Hiroaki Shime^*, Masahiko Yabu^*, Takashi Akazawa^*, Ken Kodama, Misako Matsumoto, Tsukasa Seya and Norimitsu Inoue^2,*

^* Department of Molecular Genetics and Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan; and Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Sapporo, Japan

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- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant from the Cooperative Link of Unique Science and Technology for Economy Revitalization promoted by the Ministry of Education, Culture, Sports, Science and Technology of Japan and a Grant-in-Aid for Young Scientists from the Ministry of Education, Culture, Sports, Science, and Technology.

² Address correspondence and reprint requests to Dr. Norimitsu Inoue, Department of Molecular Genetics, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka 537-8511, Japan. E-mail address: inoue-no{at}mc.pref.osaka.jp

³ Abbreviations used in this paper: DC, dendritic cell; PGN, peptidoglycan; BCG, bacillus Calmette-Guérin; CWS, cell wall skeleton; LDH, lactate dehydrogenase; MCT, monocarboxylate transporter; siRNA, small interfering RNA; Pam₃CSK₄, N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2R,S)propyl]-[R]-cysteinyl-[S]-seryl-[S]-lysl-[S]-lysl-[S]-lysl-[S]-lysine/³HCl; BCECF, 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein/acetoxymethyl ester.