title: 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: Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis University, St Louis, MO 63104, USA.
authors: Xuesong
authors: X
authors: Qian
authors: Ling
authors: L
authors: Gu
authors: Huan
authors: H
authors: Ning
authors: Yanping
authors: Y
authors: Zhang
authors: Eddy C
authors: EC
authors: Hsueh
authors: Mingui
authors: M
authors: Fu
authors: Xiaoyu
authors: X
authors: Hu
authors: Lin
authors: L
authors: Wei
authors: Daniel F
authors: DF
authors: Hoft
authors: Jianguo
authors: J
authors: Liu
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D050764:Cyclin-Dependent Kinase Inhibitor p19 / Q000235:genetics; D015232:Dinoprostone / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D053759:Interleukin-23 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism; D020218:Response Elements; D015398:Signal Transduction; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D050764:Cyclin-Dependent Kinase Inhibitor p19; D053759:Interleukin-23; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone
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