Projects per year
Abstract
BACKGROUND: IL-23 is the key cytokine for generation of pathogenic IL-17–producing helper T (TH17) cells, which contribute critically to autoimmune diseases. However, how IL-23 generates pathogenic TH17 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 TH17 cells.
METHODS: The role of PGE2 in induction of pathogenic TH17 cells was investigated in mouse TH17 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 TH17 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 TH17 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/TH17 pathway.
CONCLUSIONS: T cell–intrinsic EP2/EP4 signaling is critical in IL-23–driven generation of pathogenic TH17 cells and consequent pathogenesis in the skin.
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 TH17 cells.
METHODS: The role of PGE2 in induction of pathogenic TH17 cells was investigated in mouse TH17 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 TH17 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 TH17 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/TH17 pathway.
CONCLUSIONS: T cell–intrinsic EP2/EP4 signaling is critical in IL-23–driven generation of pathogenic TH17 cells and consequent pathogenesis in the skin.
Original language | English |
---|---|
Pages (from-to) | 631-643 |
Journal | Journal of Allergy and Clinical Immunology |
Volume | 143 |
Issue number | 2 |
Early online date | 20 Jun 2018 |
DOIs | |
Publication status | Published - 1 Feb 2019 |
Fingerprint
Dive into the research topics of 'T cell–intrinsic prostaglandin E2-EP2/EP4 signaling is critical in pathogenic TH17 cell–driven inflammation'. Together they form a unique fingerprint.Projects
- 2 Finished
-
Investigating the immune mechanisms underlying NSAID chemoprevention of colorectal cancer
1/08/18 → 31/01/22
Project: Research
-
To delineate immune mechanisms for limiting asthma development and severity
1/02/18 → 31/01/23
Project: Research