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タイトル: | Progression of autoimmune hepatitis is mediated by IL-18-producing dendritic cells and hepatic CXCL9 expression in mice. |
著者: | Ikeda, Aki Aoki, Nobuhiro Kido, Masahiro Iwamoto, Satoru Nishiura, Hisayo Maruoka, Ryutaro Chiba, Tsutomu Watanabe, Norihiko |
著者名の別形: | 池田, 亜希 渡部, 則彦 |
発行日: | Jul-2014 |
出版者: | wiley |
誌名: | Hepatology |
巻: | 60 |
号: | 1 |
開始ページ: | 224 |
終了ページ: | 236 |
抄録: | Clinical manifestations of autoimmune hepatitis (AIH) range from mild chronic to acute, sometimes fulminant hepatitis. However, it is unknown how the progression to fatal hepatitis occurs. We developed a mouse model of fatal AIH by inducing a concurrent loss of forkhead box P3(+) regulatory T cells and programmed cell death-1 (PD-1)-mediated signaling. In this model, dysregulated follicular helper T cells in the spleen are responsible for the induction, and the C-C chemokine receptor 6/C-C chemokine ligand 20 axis is crucial for the migration of these T cells into the liver. Using this fatal AIH model, we aimed to clarify key molecules triggering fatal AIH progression. During progression, T-bet together with interferon (IFN)-γ and C-X-C chemokine receptor (CXCR)3 were highly expressed in the inflamed liver, suggesting helper T (Th)1-type inflammation. T cells that dominantly expanded in the spleen and the inflamed liver were CXCR3-expressing CD8(+) T cells; depletion of these CD8(+) T cells suppressed AIH progression. Expression of one CXCR3 ligand, chemokine (C-X-C motif) ligand (CXCL)9, was elevated in the liver. CXCL9-expressing macrophages/Kupffer cells were colocalized with infiltrating T cells, and in vivo administration of anti-CXCL9 suppressed AIH progression. In addition, serum levels of interleukin (IL)-18, but not IL-1β, were elevated during progression, and dendritic cells in the spleen and liver highly produced IL-18. In vivo administration of anti-IL-18R suppressed the increase of splenic CXCR3(+) T cells and the progression to fatal AIH. Moreover, tumor necrosis factor alpha, but not IFN-γ, was involved in up-regulating CXCL9 in the liver and for increased serum levels of IL-18. |
著作権等: | This is the peer reviewed version of the following article: Ikeda, A., Aoki, N., Kido, M., Iwamoto, S., Nishiura, H., Maruoka, R., Chiba, T. and Watanabe, N. (2014), Progression of autoimmune hepatitis is mediated by IL-18-producing dendritic cells and hepatic CXCL9 expression in mice. Hepatology, 60: 224–236, which has been published in final form at http://dx.doi.org/10.1002/hep.27087. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. この論文は出版社版でありません。引用の際には出版社版をご確認ご利用ください。 This is not the published version. Please cite only the published version. |
URI: | http://hdl.handle.net/2433/199898 |
DOI(出版社版): | 10.1002/hep.27087 |
PubMed ID: | 24700550 |
出現コレクション: | 学術雑誌掲載論文等 |
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