The action of short fatty chain acid on cytokine gene regulation.

短脂肪酸对细胞因子基因调控的作用。

• 批准号: 14570400
• 负责人: AMASAKI Yoshiharu
• 金额: $ 2.24万
• 依托单位: HOKKAIDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570400/
• 关键词: Rheumatoid arthritis; TNF-α; Short chain fatty acid; inflammation; AU-rich element; 転写因子

Tumor necrosis factor-α (TNF-α) has a pivotal role in the pathogenesis of rheumatoid arthritis (RA). TNF-α is produced largely by monocyte-like synoviocytes (MLS) in the inflammatory synovium in RA, and is an important therapeutic target in RA. Butyrare is a natural product of intestinal bacterial flora and has anti-inflammatory effects of the luminal environment by inhibiting the production of TNF-α, the precise mechanism is yet unclear. In this study, butyrate suppressed TNF-α secretion by primary synoviocytes, as well as peripheral monocytes and murine RAW264.7 macrophage cells. In these cells, butyrate suppressed TNF-α mRNA expression, but did not inhibit the transnational activity driven through the TNF-α promoter. In addition, the inhibitory effect of butyrate on TNF-α mRNA expression was dependent on the AU-rich element (ARE) in 3' untranslated region (UTR) of the TNF-α transcripts, which was known to be involved in the regulation of TNF-α mRNA turnover. As a candidate molecule that mediate butyrate-dependent TNF-α mRNA inhibition, TIS11B was indicated that as the mRNA was induced in monocytes by butyrate. When TIS11B was overexpressed in monocytes, TNF-α gene induction by LPS was significantly inhibited. It was concluded that TIS11B is a candidate factor that mediates inhibitory action of butyrate on TNF-α expression.

肿瘤坏死因子-α (TNF-α)在类风湿关节炎（RA）的发病过程中起关键作用。TNF-α主要由RA炎症性滑膜中的单核细胞样滑膜细胞（MLS）产生，是RA重要的治疗靶点。丁酸盐是肠道菌群的天然产物，通过抑制TNF-α的产生对肠道环境具有抗炎作用，其确切机制尚不清楚。本研究中，丁酸盐抑制原代滑膜细胞、外周单核细胞和小鼠RAW264.7巨噬细胞分泌TNF-α。在这些细胞中，丁酸盐抑制TNF-α mRNA的表达，但不抑制通过TNF-α启动子驱动的跨国活性。此外，丁酸盐对TNF-α mRNA表达的抑制作用依赖于TNF-α转录本3'非翻译区（UTR）的富au元素（ARE），已知其参与调节TNF-α mRNA的转换。作为介导丁酸依赖性TNF-α mRNA抑制的候选分子，TIS11B被认为是丁酸在单核细胞中诱导的mRNA。当TIS11B在单核细胞中过表达时，LPS对TNF-α基因的诱导作用明显受到抑制。由此可见，TIS11B是介导丁酸盐对TNF-α表达抑制作用的候选因子。

项目成果

Saneyoshi T, Kume S, Amasaki Y, Mikoshiba K.: "The Wnt/calcium pathway activates NF-AT and promotes ventral cell fate in Xenopus embryos"Nature. 417(6886). 295-299 (2002)

Saneyoshi T、Kume S、Amasaki Y、Mikoshiba K.：“Wnt/钙途径激活 NF-AT 并促进非洲爪蟾胚胎中的腹侧细胞命运”Nature。

Takeuchi R, Atsumi T, Ieko M, Amasaki Y, Ichikawa K, Koike T.: "Suppressed intrinsic fibrinolytic activity by monoclonal anti-beta-2 glycoprotein I autoantibodies : possible mechanism for thrombosis in antiphospholipid syndrome."Br J Haematol. 119(3). 781

Takeuchi R、Atsumi T、Ieko M、Amasaki Y、Ichikawa K、Koike T.：“单克隆抗 β-2 糖蛋白 I 自身抗体抑制内在纤溶活性：抗磷脂综合征中血栓形成的可能机制。”Br J Haematol。

Takeuchi R, Atsumi T, Ieko M, Amasaki Y, Ichikawa K, Koike T.: "Suppressed intrinsic fibrinolytic activity by monoclonal anti-beta-2 glycoprotein I autoantibodies : possible mechanism for thrombosis in patients with antiphospholipid syndrome."Br J Haemato

Takeuchi R、Atsumi T、Ieko M、Amasaki Y、Ichikawa K、Koike T.：“单克隆抗 β-2 糖蛋白 I 自身抗体抑制内在纤溶活性：抗磷脂综合征患者血栓形成的可能机制。”Br J Haemato

Amasaki Y, Adachi S, Ishida Y, Iwata M, Arai N, Arai K, Miyatake S.: "A constitutively nuclear form of NFATx shows efficient transactivation activity and induces differentiation of CD4(+)CD8(+) T cells."J Biol Chem.. 277. 25640-25648 (2002)

Amasaki Y、Adachi S、Ishida Y、Iwata M、Arai N、Arai K、Miyatake S.：“NFATx 的组成型核形式显示出有效的反式激活活性，并诱导 CD4( )CD8( ) T 细胞的分化。” J Biol Chem

Yasuda S, Atsumi T, Ieko M, Matsuura E, Amasaki Y, et al.: "Nicked beta2-glycoprotein I : A marker of cerebral infarct and a novel role in the negative feedback pathway of extrinsic fibrinolysis."Blood. (in press). (2004)

Yasuda S、Atsumi T、Ieko M、Matsuura E、Amasaki Y 等人：“带缺口的 β2-糖蛋白 I：脑梗塞的标志物以及外源性纤溶负反馈途径中的新作用。”血液。