Deletion of interleukin-6 in monocytes/macrophages suppresses the initiation of hepatocellular carcinoma in mice.
Deletion of interleukin-6 in monocytes/macrophages suppresses the initiation of hepatocellular carcinoma in mice.
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单核细胞/巨噬细胞中白细胞介素 6 的缺失可抑制小鼠肝细胞癌的发生。
DOI：
10.1186/s13046-016-0412-1
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发表时间：
2016-09-02
期刊：
影响因子：
--
通讯作者：
Yang J
中科院分区：
文献类型：
--
作者：
Kong L;Zhou Y;Bu H;Lv T;Shi Y;Yang J
肝细胞癌（HCC）与炎症有关，全球大约30%的人口显示出目前或过去感染乙型或丙型肝炎病毒的血清学证据。常驻肝巨噬细胞被称为Kupffer细胞（KCs），被认为是HCC的特异性肿瘤相关巨噬细胞（tam），可以产生多种细胞因子，最重要的是白细胞介素(IL)-6，促进HCC的肿瘤发生。然而，KCs和IL-6在肝脏癌变中的作用尚不清楚。我们分析了192例患者的白细胞相关外周血数据，并构建了小鼠模型，通过照射清除骨髓，利用il -6缺陷小鼠捐献的骨髓进行重建，以进一步阐明毒性攻击和致癌基因突变对肝脏的病理改变。HCC患者外周血单核细胞计数和血清IL-6水平明显高于非HCC患者。此外，不同组织病理分级个体间IL-6水平有显著差异。在选择性IL-6消融单核细胞/KCs的小鼠中，我们观察到中毒性肝损伤、炎症浸润和全身炎症减轻。在自发发生HCC的mdr2缺陷小鼠中，单核细胞/KCs中IL-6的缺失导致IL-6/信号换能器和转录信号激活因子的抑制，血清IL-6水平降低，肿瘤发生延迟。我们的研究结果表明，tam衍生的IL-6增加对炎症反应具有放大作用，从而促进HCC的发生和发展。
Hepatocellular carcinoma (HCC) is associated with inflammation, and roughly 30 % of the global population shows serological evidence of current or past infection with hepatitis B or hepatitis C virus. Resident hepatic macrophages, known as Kupffer cells (KCs), are considered as the specific tumor-associated macrophages (TAMs) of HCC, and can produce various cytokines—most importantly interleukin (IL)-6—to promote tumorigenesis of HCC. However, the roles of KCs and IL-6 in carcinogenesis in the liver are still unclear. We analyzed leukocyte-related peripheral blood data of 192 patients and constructed a mouse model in which the bone marrow was cleared out by irradiation and reconstructed using bone marrow donated from IL-6-deficient mice to further elucidate the hepatic pathological changes in response to toxic challenge and oncogenic gene mutation. Peripheral monocyte counts and serum IL-6 levels were significantly higher in patients with HCC than in those without HCC. In addition, there was a significant difference in the levels of IL-6 among individuals with different histopathological grades. In mice with selective IL-6 ablation in monocytes/KCs, we observed decreased toxic liver injury, inflammatory infiltration, and systemic inflammation. In Mdr2-deficient mice, which spontaneously developed HCC, the loss of IL-6 in monocytes/KCs resulted in inhibition of IL-6/signal transducer and activator of transcription 3 signaling, decreased serum IL-6 levels, and delayed tumorigenesis. Our findings demonstrate that increased TAM-derived IL-6 had an amplifying effect on the inflammation response, thereby promoting the occurrence and development of HCC.
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影响因子：
50.3
作者：
Bromberg J;Wang TC
通讯作者：
Wang TC
DOI：
10.1046/j.1440-1746.1999.01903.x
发表时间：
1999-05-01
影响因子：
4.1
作者：
Imperial, JC
通讯作者：
Imperial, JC
影响因子：
3.8
作者：
Hsia, C. -Y.;Huo, T-I.;Lee, S. -D.
通讯作者：
Lee, S. -D.
影响因子：
3.8
作者：
Harstad, EB;Klaassen, CD
通讯作者：
Klaassen, CD
影响因子：
13.5
作者：
Blindenbacher, A;Wang, XY;Heim, MH
通讯作者：
Heim, MH