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タイトル: | T cell-intrinsic prostaglandin E2-EP2/EP4 signaling is critical in pathogenic TH17 cell-driven inflammation |
著者: | Lee, Jinju Aoki, Tomohiro Thumkeo, Dean Siriwach, Ratklao Yao, Chengcan Narumiya, Shuh |
著者名の別形: | 李, 震珠 青木, 友浩 タムケオ, ディーン 成宮, 周 |
キーワード: | Psoriasis pathogenic TH17 cells IL-23 receptor prostaglandin E2 prostaglandin E receptor EP2 prostaglandin E receptor EP4 signal transducer and activator of transcription 3 cAMP-responsive element binding protein 1 nuclear factor κ light chain enhancer of activated B cells |
発行日: | Feb-2019 |
出版者: | Elsevier BV |
誌名: | Journal of Allergy and Clinical Immunology |
巻: | 143 |
号: | 2 |
開始ページ: | 631 |
終了ページ: | 643 |
抄録: | 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. |
記述: | PGE2経路による病因細胞Th17の増殖機構を解明 --乾癬の慢性的な皮膚炎症を改善する新しい治療薬開発に向けて--. 京都大学プレスリリース. 2018-06-20. |
著作権等: | © 2018 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
URI: | http://hdl.handle.net/2433/236490 |
DOI(出版社版): | 10.1016/j.jaci.2018.05.036 |
PubMed ID: | 29935220 |
関連リンク: | https://www.kyoto-u.ac.jp/ja/research-news/2018-06-20 |
出現コレクション: | 学術雑誌掲載論文等 |
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