T cell-intrinsic prostaglandin E2-EP2/EP4 signaling is critical in pathogenic TH17 cell-driven inflammation

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 T(H)d17 cells remains to be elucidated. Objectives: We sought to examine the involvement, molecular mechanisms, and clinical implications of prostaglandin ( PG) E-2-EP2/EP4 signaling in induction of IL-23-driven pathogenic T(H)17 cells. Methods: The role of PGE(2) in induction of pathogenic T(H)17 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 PGE(2)-EP2/EP4 signaling in psoriatic skin from patients. Results: IL-23 induces Ptgs2, encoding COX2 in T(H)17 cells, and produces PGE(2), 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-kappa B) through cyclic AMP-protein kinase A signaling. This PGE(2) signaling also induces expression of various inflammation-related genes, which possibly function in T(H)17 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 PGE(2) signaling and the IL-23/T(H)17 pathway. Conclusions: T cell-intrinsic EP2/EP4 signaling is critical in IL-23-driven generation of pathogenic T(H)17 cells and consequent pathogenesis in the skin.