1. T cell-intrinsic prostaglandin E 2 -EP2/EP4 signaling is critical in pathogenic T H 17 cell-driven inflammation.
- Author
-
Lee J, Aoki T, Thumkeo D, Siriwach R, Yao C, and Narumiya S
- Subjects
- Animals, Cells, Cultured, Cyclic AMP metabolism, Dinoprostone metabolism, Disease Models, Animal, Gene Expression Profiling, Humans, Imiquimod, Interleukin-23 metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptors, Prostaglandin E, EP2 Subtype genetics, Receptors, Prostaglandin E, EP4 Subtype genetics, Signal Transduction, Inflammation immunology, Psoriasis immunology, Receptors, Prostaglandin E, EP2 Subtype metabolism, Receptors, Prostaglandin E, EP4 Subtype metabolism, Th17 Cells immunology
- Abstract
Background: IL-23 is the key cytokine for generation of pathogenic IL-17-producing helper T (T
H 17) cells, which contribute critically to autoimmune diseases. However, how IL-23 generates pathogenic TH 17 cells remains to be elucidated., Objectives: We sought to examine the involvement, molecular mechanisms, and clinical implications of prostaglandin (PG) E2 -EP2/EP4 signaling in induction of IL-23-driven pathogenic TH 17 cells., Methods: The role of PGE2 in induction of pathogenic TH 17 cells was investigated in mouse TH 17 cells in culture in vitro and in an IL-23-induced psoriasis mouse model in vivo. Clinical relevance of the findings in mice was examined by using gene expression profiling of IL-23 and PGE2 -EP2/EP4 signaling in psoriatic skin from patients., Results: IL-23 induces Ptgs2, encoding COX2 in TH 17 cells, and produces PGE2 , which acts back on the PGE receptors EP2 and EP4 in these cells and enhances IL-23-induced expression of an IL-23 receptor subunit gene, Il23r, by activating signal transducer and activator of transcription (STAT) 3, cAMP-responsive element binding protein 1, and nuclear factor κ light chain enhancer of activated B cells (NF-κB) through cyclic AMP-protein kinase A signaling. This PGE2 signaling also induces expression of various inflammation-related genes, which possibly function in TH 17 cell-mediated pathology. Combined deletion of EP2 and EP4 selectively in T cells suppressed accumulation of IL-17A+ and IL-17A+ IFN-γ+ pathogenic Th17 cells and abolished skin inflammation in an IL-23-induced psoriasis mouse model. Analysis of human psoriatic skin biopsy specimens shows positive correlation between PGE2 signaling and the IL-23/TH 17 pathway., Conclusions: T cell-intrinsic EP2/EP4 signaling is critical in IL-23-driven generation of pathogenic TH 17 cells and consequent pathogenesis in the skin., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2019
- Full Text
- View/download PDF