Tumor-secreted lactic acid promotes IL-23/IL-17 proinflammatory pathway
Tumor-secreted lactic acid promotes IL-23/IL-17 proinflammatory pathway
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DOI：
10.4049/jimmunol.180.11.7175
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发表时间：
2008-06-01
影响因子：
4.4
通讯作者：
Inoue, Norimitsu
中科院分区：
文献类型：
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作者：
Shime, Hiroaki;Yabu, Masahiko;Inoue, Norimitsu
IL-23是一种促炎细胞因子，由一个p19亚基和一个p40亚基组成，与IL-12共享。IL-23在肿瘤组织内及周围过表达，诱导局部炎症，促进肿瘤发展。许多肿瘤细胞通过改变其葡萄糖代谢产生大量乳酸。在这项研究中，我们发现肿瘤细胞分泌的乳酸在TLR2和4配体刺激的单核/巨噬细胞和肿瘤浸润免疫细胞中增强IL-23p19的转录和IL-23的产生。在人IL-23p19基因的2.7 kb 5'侧区检测到负责乳酸增强活性的DNA元件。乳酸的作用受到细胞外ph的严格调节。此外，乳酸通过诱导IL-23过量产生，促进了TLR配体刺激的小鼠脾细胞ag依赖性的促炎细胞因子IL-17的分泌，而不是ifn - γ。有趣的是，即使在没有TLR配体刺激的情况下也能观察到这种效应。这些结果表明，乳酸不仅仅是一种终端代谢物，它还是一种促炎介质，由肿瘤细胞分泌，激活IL-23/IL-17促炎途径，而不是Th1途径。靶向乳酸诱导的促炎反应可能是治疗癌症的有效途径。
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.