论文摘要
目的:观察外源性白细胞介素-10（IL-10）对转化生长因子β1（TGF-β1）刺激的大鼠原代肝星状细胞（HSC）活化状态及其信号转导通路的影响,探讨外源性IL-10抗肝纤维化作用的可能机制。方法:采用链霉蛋白酶E、IV型胶原酶灌注和振荡消化离体的大鼠肝脏, Nycodenz密度梯度离心分离HSC,鉴定细胞活率及纯度。TGFβ1处理不同培养时段的HSC,观察细胞形态,检测α-肌动蛋白（α-SMA）表达,选择对TGFβ1的刺激活化反应最敏感时段的HSC为细胞模型。检测不同浓度的IL-10对TGF-β1刺激的HSC表达α-SMA的影响,筛选1个适合的IL-10处理浓度进行研究。对空白组（C组）、IL-10处理组（I组）、TGFβ1处理组（T组）及IL-10与TGFβ1共处理组（M组）分别处理48小时,比较各组细胞形态,α-SMA、Ⅰ型前胶原,TGFβR-Ⅰ、TGFβR-Ⅱ,Smad3、Smad4、Smad7蛋白表达的差异。结果:建立一种简便、有效的大鼠肝星状细胞分离方法,分离培养的大鼠原代HSC活率在90%以上,纯度超过90%。TGFβ1处理可促进培养2,3,4,5天的HSC活化,以对培养第3天的细胞作用最明显,其α-SMA表达增加78.05%,而培养6,7天的HSC的α-SMA表达和细胞形态变化不明显。大于20μg/L的IL-10对TGFβ1刺激的HSC表达α-SMA有抑制作用。进一步研究显示T组α-SMA、Ⅰ型前胶原、Smad3表达比C组高（P<0.05）,M组HSC表达α-SMA、Ⅰ型前胶原、Smad3比T组低（P<0.05）,而各组间的TGFβR-Ⅰ、TGFβR-Ⅱ、Smad4和Smad7表达无明显差异（P>0.05）。结论:原代大鼠HSC在体外培养过程中,TGFβ1促进处于部分活化状态HSC的活化,完全活化的HSC对TGFβ1的刺激活化作用不敏感。IL-10通过影响HSC胞内TGF-β1/Smad信号转导抑制HSC的活化和胶原的合成,发挥抗肝纤维化作用。其主要机理在于抑制Smad3蛋白的表达,而与TGFβR-Ⅰ、TGFβR-Ⅱ、Smad4、Smad7表达无关。
论文目录
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