| First Author | Lee J | Year | 2019 |
| Journal | J Allergy Clin Immunol | Volume | 143 |
| Issue | 2 | Pages | 631-643 |
| PubMed ID | 29935220 | Mgi Jnum | J:332323 |
| Mgi Id | MGI:6835471 | Doi | 10.1016/j.jaci.2018.05.036 |
| Citation | Lee J, et al. (2019) T cell-intrinsic prostaglandin E2-EP2/EP4 signaling is critical in pathogenic TH17 cell-driven inflammation. J Allergy Clin Immunol 143(2):631-643 |
| abstractText | 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 kappa light chain enhancer of activated B cells (NF-kappaB) 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-gamma(+) 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. |
