IL-23-dependent and -independent enhancement pathways of IL-17A production by lactic acid.
Interleukin-17A (IL-17A) is a cytokine produced by T(h)17 cells that plays an important role in inflammatory and autoimmune diseases and cancer. Stimulation with IL-6, transforming growth factor-β , IL-21, IL-1β and IL-23 is required for differentiation of T(h)17 cells and the production of IL-17A. Recently, we reported that tumor-derived lactic acid enhances the toll-like receptor (TLR) ligand-mediated expression of IL-23, leading to increased IL-17A production. Tumor cells secrete large amounts of lactic acid due to the up-regulation of glycolysis, which is known as the Warburg effect. Even without TLR ligand stimulation, lactic acid enhanced antigen-dependent IL-17A production from splenocytes in an IL-23-dependent manner. Here, we show that macrophages and effector/memory CD4(+) T cells are the primary cell types involved in the ability of lactic acid to boost IL-17A production. Although lactic acid suppressed the proliferation of T(h)1 and T(h)17 cells, T(h)17 cells still secreted large amounts of IL-17A. CD40 ligand-CD40 interactions were involved in the up-regulation of IL-17A by lactic acid through IL-12/23p40 production. A new cytokine containing the IL-12/23p40 subunit, but not IL-23, IL-12 or the IL-12p40 homodimer, is a candidate for involvement in the up-regulation of IL-17A. IL-1β also increased IL-17A expression; however, IL-1β, CARD9 and MyD88 signaling pathways activated by known intrinsic inflammatory mediators were hardly required for the enhanced activity induced by lactic acid. Our results show that lactic acid functions as an intrinsic inflammatory mediator that activates IL-23-dependent and -independent pathways, resulting in the promotion of chronic inflammation in tumor microenvironments.
Department of Molecular Genetics, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Osaka, Osaka 537-8511, Japan.
Masahiko
M
Yabu
Hiroaki
H
Shime
Hiromitsu
H
Hara
Takashi
T
Saito
Misako
M
Matsumoto
Tsukasa
T
Seya
Takashi
T
Akazawa
Norimitsu
N
Inoue
D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D007156:Immunologic Memory; D053762:Interleukin-12 Subunit p40 / Q000276:immunology*; D020381:Interleukin-17 / Q000096:biosynthesis*; D053759:Interleukin-23 / Q000737:chemistry / Q000276:immunology*; D019344:Lactic Acid / Q000276:immunology* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology*; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation
D039481:CD11b Antigen; D053762:Interleukin-12 Subunit p40; D020381:Interleukin-17; D053759:Interleukin-23; D019344:Lactic Acid