T cell–intrinsic prostaglandin E(2)-EP2/EP4 signaling is critical in pathogenic T(H)17 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)17 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 T(H)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 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 κ light chain enhancer of activated B cells (NF-κB) 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-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 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.