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

Abstract

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.

• Authors: Xuesong Qian, Ling Gu, Huan Ning, Yanping Zhang, Eddy C Hsueh, Mingui Fu, Xiaoyu Hu, Lin Wei, Daniel F Hoft, Jianguo Liu
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 190 Issue 11 Pg. 5894-902 (Jun 01 2013) ISSN: 1550-6606 [Electronic] United States
• PMID: 23645882 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclin-Dependent Kinase Inhibitor p19
• Interleukin-23
• Receptors, Prostaglandin E, EP2 Subtype
• Receptors, Prostaglandin E, EP4 Subtype
• Cyclic AMP
• Cyclic AMP-Dependent Protein Kinases
• Dinoprostone

Topics

• Animals
• Breast Neoplasms (immunology, 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, metabolism)
• Mice
• Neoplasms (genetics, immunology, metabolism)
• Promoter Regions, Genetic
• Receptors, Prostaglandin E, EP2 Subtype (metabolism)
• Receptors, Prostaglandin E, EP4 Subtype (metabolism)
• Response Elements
• Signal Transduction
• Th17 Cells (immunology, metabolism)
• Transcription, Genetic
• Tumor Microenvironment (immunology)