Increased Th17 cells in the tumor microenvironment is mediated by IL-23 via tumor-secreted prostaglandin E2

• Published in: The Journal of immunology (1950) Vol. 190; no. 11; pp. 5894 - 5902
• Main Authors: Qian, Xuesong, Gu, Ling, Ning, Huan, Zhang, Yanping, Hsueh, Eddy C, Fu, Mingui, Hu, Xiaoyu, Wei, Lin, Hoft, Daniel F, Liu, Jianguo
• Format: Journal Article
• Language: English
• Published: United States 01-06-2013
• Subjects: Animals; Breast Neoplasms - immunology; Breast Neoplasms - metabolism; Cell Line; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Cyclin-Dependent Kinase Inhibitor p19 - genetics; Dinoprostone - metabolism; Female; Gene Expression; Interleukin-23 - genetics; Interleukin-23 - metabolism; Mice; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - metabolism; Promoter Regions, Genetic; Receptors, Prostaglandin E, EP2 Subtype - metabolism; Receptors, Prostaglandin E, EP4 Subtype - metabolism; Response Elements; Signal Transduction; Th17 Cells - immunology; Th17 Cells - metabolism; Transcription, Genetic; Tumor Microenvironment - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1203141

Tumor cell-derived molecules such as cytokines and lipid mediators play a critical role in inducing chronic inflammation in the tumor microenvironment. We found that Th17 cells were increased in the peripheral blood, spleen, and tumor tissues of mammary gland tumor-bearing mice. The Th17 cell survival factor, IL-23, was also overexpressed in tumor tissues isolated from mice and human breast cancer patients. Soluble molecules secreted from breast tumor cells, but not normal breast epithelial cells, induced IL-23 protein secretion in dendritic cells via induction of p19 mRNA expression. Our data further indicate that tumor-secreted PGE2 through EP2 and EP4 receptors enhanced IL-23 p19 gene transcription through binding to the cAMP-response element in the p19 promoter. Blocking PGE2 synthesis by NS398, a COX2 inhibitor, abrogated the enhancement of p19 expression both in vitro and in vivo. Furthermore, blocking protein kinase A (PKA) by H89 completely abrogated the inductive effects of tumor-conditioned medium and PGE2 on p19 transcription, whereas the cAMP active analog, Forskolin, mimics the PGE2 effect. Taken together, our results indicate that tumor-secreted PGE2 induces IL-23, but not IL-12, production in the tumor microenvironment, leading to Th17 cell expansion. This inductive effect of PGE2 on IL-23 p19 transcription is mediated through cAMP/PKA signaling transduction pathway.