CCL5/RANTES 在慢性肝病期间促进 HCC 进展的功能作用。
Functional role of CCL5/RANTES for HCC progression during chronic liver disease.
机构信息
Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
Merck Serono Geneva Research Centre, Case postale 54, chemin des Mines 9, Geneva CH-1211 20, Switzerland.
出版信息
J Hepatol. 2017 Apr;66(4):743-753. doi: 10.1016/j.jhep.2016.12.011. Epub 2016 Dec 21.
BACKGROUND & AIMS: During liver inflammation, triggering fibrogenesis and carcinogenesis immune cells play a pivotal role. In the present study we investigated the role of CCL5 in human and in murine models of chronic liver inflammation leading to hepatocellular carcinoma (HCC) development.
METHODS
CCL5 expression and its receptors were studied in well-defined patients with chronic liver disease (CLD) and in two murine inflammation based HCC models. The role of CCL5 in inflammation, fibrosis, tumor initiation and progression was analyzed in different cell populations of NEMO/CCL5 animals and after bone marrow transplantation (BMT). For therapeutic intervention Evasin-4 was injected for 24h or 8weeks.
RESULTS
In CLD patients, CCL5 and its receptor CCR5 are overexpressed - an observation confirmed in the Mdr2 and NEMO model. CCL5 deletion in NEMO mice diminished hepatocyte apoptosis, compensatory proliferation and fibrogenesis due to reduced immune cell infiltration. Especially, CD45/Ly6G granulocytes, CD45/CD11b/Gr1.1/F4/80 pro-inflammatory monocytes, CD4 and CD8 T cells were decreased. One year old NEMO/CCL5 mice displayed smaller and less malignant tumors, characterized by reduced proliferative capacity and less pronounced angiogenesis. We identified hematopoietic cells as the main source of CCL5, while CCL5 deficiency did not sensitise NEMO hepatocytes towards TNFα induced apoptosis. Finally, therapeutic intervention with Evasin-4 over a period of 8weeks ameliorated liver disease progression.
CONCLUSION
We identified an important role of CCL5 in human and functionally in mice with disease progression, especially HCC development. A novel approach to inhibit CCL5 in vivo thus appears encouraging for patients with CLD.
LAY SUMMARY
Our present study identifies the essential role of the chemoattractive cytokine CCL5 for liver disease progression and especially hepatocellular carcinoma development in men and mice. Finally, the inhibition of CCL5 appears to be encouraging for therapy of human chronic liver disease.
背景与目的
在肝脏炎症过程中，触发纤维化和癌变的免疫细胞起着关键作用。本研究旨在探讨 CCL5 在导致肝细胞癌（HCC）发展的慢性肝炎症人类和小鼠模型中的作用。
方法
在明确诊断的慢性肝病（CLD）患者和两种基于炎症的 HCC 小鼠模型中，研究了 CCL5 的表达及其受体。在 NEMO/CCL5 动物的不同细胞群中和骨髓移植（BMT）后，分析了 CCL5 在炎症、纤维化、肿瘤起始和进展中的作用。为了进行治疗干预，在 24 小时或 8 周内注射了 Evasin-4。
结果
在 CLD 患者中，CCL5 及其受体 CCR5 过度表达——这一观察结果在 Mdr2 和 NEMO 模型中得到了证实。NEMO 小鼠中 CCL5 的缺失减少了肝细胞凋亡、代偿性增殖和纤维化，这是由于免疫细胞浸润减少所致。特别是 CD45/Ly6G 粒细胞、CD45/CD11b/Gr1.1/F4/80 促炎单核细胞、CD4 和 CD8 T 细胞减少。一岁的 NEMO/CCL5 小鼠显示出更小、更少恶性的肿瘤，其特征是增殖能力降低和血管生成程度降低。我们确定了造血细胞是 CCL5 的主要来源，而 CCL5 缺失不会使 NEMO 肝细胞对 TNFα 诱导的凋亡敏感。最后，用 Evasin-4 进行 8 周的治疗干预改善了肝病进展。
结论
我们在人类和功能上在疾病进展的小鼠中发现了 CCL5 的重要作用，特别是 HCC 的发展。因此，体内抑制 CCL5 的新方法似乎对 CLD 患者有希望。
平铺直叙
本研究确定了趋化因子 CCL5 在人类和小鼠慢性肝病进展、特别是肝细胞癌发展中的重要作用。最后，抑制 CCL5 似乎对治疗人类慢性肝病有希望。
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