Immune stimulation of hepatic fibrogenesis by CD8 cells and attenuation by transgenic interleukin-10 from hepatocytes
Immune stimulation of hepatic fibrogenesis by CD8 cells and attenuation by transgenic interleukin-10 from hepatocytes
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DOI：
10.1053/j.gastro.2004.04.062
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发表时间：
2004-09-01
期刊：
影响因子：
29.4
通讯作者：
Friedman, SL
中科院分区：
文献类型：
--
作者：
Safadi, R;Ohta, M;Friedman, SL
背景与目的：免疫调节细胞因子，包括白细胞介素-10 (IL-10)，可能介导肝纤维化。方法：采用转基因（TG）小鼠肝细胞表达大鼠IL-10 (rIL-10)，评估其对四氯化碳（CCl4）或硫代乙酰胺（TAA）肝损伤后淋巴细胞亚群和肝星状细胞活化的影响。结果：两种模型中TG动物的纤维化程度均有所减轻，这并不能完全由肝损伤程度的差异来解释。通过荧光活化细胞分选仪（FACS）发现，初始TG小鼠的CD4+ T细胞较少，并且在纤维化诱导后，CD4+ T细胞仅在野生型（WT）小鼠中减少，而在WT动物中CD8+ T细胞的增加在TG小鼠中显著减弱。在WT组和TG组中，次全照射同样减少了纤维化，表明rIL-10的抗纤维化作用是淋巴细胞介导的。为了评估淋巴细胞在星状细胞活化中的作用，我们将患有CCl4纤维化的WT动物的全脾淋巴细胞、CD4+或CD8+ t细胞亚群过代转移到严重联合免疫缺陷（SCID）受体，通过转化生长因子(TGF)- β 1和胶原I信使RNA （mRNA）的表达和α -平滑肌肌动蛋白的免疫印迹来评估星状细胞活化和纤维化刺激。此外，血清转氨酶水平和星状细胞活化mRNA在CD8+ t细胞受体中显著升高。结论：在肝脏中转基因表达rIL-10可导致未治疗和纤维化诱导后肝脏纤维化减少和肝淋巴细胞亚群改变。在这个模型中，纤维化可能是一种CD8+ tell介导的疾病，被rIL-10减弱。
Backgrounds & Aims: Immunomodulatory cytokines, including interleukin-10 (IL-10), may mediate hepatic fibrosis. Methods: We generated transgenic (TG) mice with hepatocyte expression of rat IL-10 (rIL-10) to assess its impact on lymphocyte subsets and activation of hepatic stellate cells following liver injury from carbon tetrachloride (CCl4) or thioacetamide (TAA). Results: Fibrosis was reduced in the TG animals in both models, which was not explained solely by differences in liver injury. By fluorescence-activated cell sorter (FACS), there were less CD4+ T cells in naive TG mice, and, following fibrosis induction, CD4+ T cells decreased only in wild-type (WT) mice, whereas increases in CD8+ T cells seen in WT animals were significantly attenuated in TG mice. Subtotal irradiation diminished fibrosis equally in both WT and TG groups, suggesting that rIL-10's antifibrotic effect was lymphocyte mediated. To assess the role of lymphocytes on stellate cell activation, either whole splenic lymphocytes, CD4+, or CD8+ T-cell subsets from WT animals with CCl4 fibrosis were adoptively transferred to severe combined immunodeficiency (SCID) recipients, which led to stellate cell activation and fibrogenic stimulation as assessed by expression of transforming growth factor (TGF)-beta1 and collagen I messenger RNA (mRNA) and by immunoblot of alpha-smooth muscle actin. Moreover, serum aminotransferase levels and stellate cell activation mRNA were significantly higher among the CD8+ T-cell recipients. Conclusions: Transgenic expression of rIL-10 in liver leads to reduced fibrosis and alterations in liver lymphocyte subsets both in untreated liver and following fibrosis induction. In this model, fibrosis may be a CD8+ Tell-mediated disease that is attenuated by rIL-10.