Department of Molecular Genetics, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Osaka, Osaka 537-8511, Japan.
Int Immunol. 2011 Jan;23(1):29-41. doi: 10.1093/intimm/dxq455. Epub 2010 Dec 3.
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.
白细胞介素-17A（IL-17A）是一种由 Th17 细胞产生的细胞因子，在炎症和自身免疫性疾病以及癌症中发挥重要作用。Th17 细胞的分化和 IL-17A 的产生需要 IL-6、转化生长因子-β、IL-21、IL-1β 和 IL-23 的刺激。最近，我们报道肿瘤衍生的乳酸增强了 Toll 样受体（TLR）配体介导的 IL-23 的表达，导致 IL-17A 产生增加。由于糖酵解的上调，肿瘤细胞会分泌大量的乳酸，这被称为沃伯格效应。即使没有 TLR 配体刺激，乳酸也以 IL-23 依赖的方式增强了抗原依赖性脾细胞中 IL-17A 的产生。在这里，我们表明巨噬细胞和效应/记忆 CD4+T 细胞是乳酸增强 IL-17A 产生能力的主要细胞类型。尽管乳酸抑制了 Th1 和 Th17 细胞的增殖，但 Th17 细胞仍分泌大量的 IL-17A。CD40 配体-CD40 相互作用通过 IL-12/23p40 产物参与了乳酸对 IL-17A 的上调。一种含有 IL-12/23p40 亚基的新型细胞因子，但不含有 IL-23、IL-12 或 IL-12p40 同源二聚体，可能参与了 IL-17A 的上调。IL-1β 也增加了 IL-17A 的表达；然而，对于乳酸诱导的增强活性，IL-1β、CARD9 和 MyD88 信号通路（由已知的固有炎症介质激活）几乎不需要。我们的结果表明，乳酸作为一种内在的炎症介质，激活了 IL-23 依赖和非依赖途径，导致肿瘤微环境中慢性炎症的促进。
