IL-23 generates pathogenic Th17 cells by triggering T cell-intrinsic prostaglandin E2-EP2/EP4 signaling

[Speaker] Jinju Lee:1
[Co-author] Dean Thumkeo:1,2, Tomohiro Aoki:2, Ratklao Siriwach:1, Chengcan Yao:3, Shuh Narumiya:1,2
1:Drug Discovery Department, Kyoto University, Japan, 2:Center for Innovation in Immunoregulation Technology and Therapeutics, Kyoto University Graduate School of Medicine, Japan, 3:Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, UK

Interleukin-23 (IL-23) is the key cytokine for generation of pathogenic IL-17-producing helper T (Th17) cells that critically contribute to autoimmune diseases and cancer. However, how IL-23 generates pathogenic Th17 cells remains to be elucidated. Here we show that IL-23 induces cyclooxygenase 2 in Th17 cells and produces prostaglandin (PG) E2, which acts back on PGE2 receptors EP2 and EP4 in Th17 cells, and enhances IL-23-induced expression of IL-23 receptor by activating CREB1 and NF-κB together with STAT3 through cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling. This signaling also induces expression of various pathogenic candidate genes. Combined deletion of EP2 and EP4 selectively in T cells abolishes inflammation in the IL-23-induced mouse model of psoriasis with suppression of accumulation of IL-17A+ and IL-17A+IFN-γ+ T cells in the lesion. The role of PGE2 in induction of pathogenic Th17 was investigated in mouse Th17 cells in culture in vitro and in IL-23-induced psoriasis mouse model in vivo. Finally, Clinical relevance of findings in mice was examined by gene expression profiling of IL-23 and PGE2-EP2/EP4 signaling in psoriatic skin from patients. Human psoriatic skin biopsies show positive correlation between PGE2 signaling and the IL-23/Th17 pathway. The T cell-intrinsic EP2/EP4 signaling is thus critical in IL-23-driven Th17 cell pathogenesis, which is amenable to therapeutic intervention.
Advanced Search