IL-34 and Macrophage Colony-Stimulating Factor Are Overexpressed in Hepatitis C Virus Fibrosis and Induce Profibrotic Macrophages That Promote Collagen Synthesis by Hepatic Stellate Cells
IL-34 and Macrophage Colony-Stimulating Factor Are Overexpressed in Hepatitis C Virus Fibrosis and Induce Profibrotic Macrophages That Promote Collagen Synthesis by Hepatic Stellate Cells
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DOI：
10.1002/hep.27328
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发表时间：
2014-12-01
期刊：
影响因子：
13.5
通讯作者：
Jeannin, Pascale
中科院分区：
文献类型：
--
作者：
Preisser, Laurence;Miot, Charline;Jeannin, Pascale
慢性丙型肝炎病毒（HCV）感染的特征是进行性肝纤维化，这是一个依赖于单核细胞募集和积聚到肝脏中的过程。在慢性损伤的肝脏中表达的控制人单核细胞分化为促纤维化巨噬细胞（Mu）的介质仍然定义不清。我们报告说，慢性HCV感染的高纤维化阶段的患者有较高的血清巨噬细胞集落刺激因子（M-CSF）和白细胞介素（IL）234水平比HCV感染的低纤维化阶段的患者和健康受试者。免疫组化显示肝损伤周围的肝细胞强烈表达IL-34和M-CSF。此外，HCV感染和炎性细胞因子增强肝细胞体外产生IL-34和M-CSF。我们接下来分析了用M-CSF（M-CSF-Mu）或IL-34（IL-34-Mu）产生的Mu对促纤维化性质的获得。M-CSF和IL-34通过分化单核细胞上调趋化因子（C-C基序）配体（CCL）2、CCL 4、C-C趋化因子受体（CCR）1和CCR 5的表达，这些因子参与肝脏病变中单核细胞募集/Mu蓄积。M-CSF-Mu和IL-34-Mu还表达肝星状细胞（HSC）激活剂、血小板衍生生长因子、转化生长因子β和半乳糖凝集素-3。IL-34-Mu和M-CSF-Mu诱导HSC（肝纤维化中主要的胶原产生细胞）的I型胶原合成。IL-13的表达与HCV感染患者的纤维化阶段相关，通过IL-34-Mu和M-CSF-Mu降低胶原酶、基质金属蛋白酶1的表达，从而增强胶原合成。通过抑制活化的自然杀伤细胞产生干扰素-γ（IFN-c），IL 34- Mu和M-CSF-Mu阻止IFN-c诱导的HSC杀伤。结论：这些结果确定M-CSF和IL-34是HCV肝纤维化的有效促纤维化因子。
Chronic hepatitis C virus (HCV) infection is characterized by progressive hepatic fibrosis, a process dependent on monocyte recruitment and accumulation into the liver. The mediators expressed in chronically injured liver that control the differentiation of human monocytes into profibrotic macrophages (Mu) remain poorly defined. We report that chronically HCV-infected patients with high fibrosis stages have higher serum levels of macrophage colony-stimulating factor (M-CSF) and interleukin (IL) 234 than HCV-infected patients with lower fibrosis stages and healthy subjects. Immunohistochemistry reveals an intense expression of IL-34 and M-CSF by hepatocytes around liver lesions. In addition, HCV infection and inflammatory cytokines enhance the in vitro production of IL-34 and M-CSF by hepatocytes. We next analyzed the acquisition of profibrotic properties by Mu generated with M-CSF (M-CSF-Mu) or IL-34 (IL-34-Mu). M-CSF and IL-34 up-regulate the expression, by differentiating monocytes, of chemokine (C-C motif) ligand (CCL) 2, CCL4, C-C chemokine receptor (CCR) 1, and CCR5, which are involved in monocyte recruitment/Mu accumulation in liver lesions. M-CSF-Mu and IL-34-Mu also express the hepatic stellate cell (HSC) activators, platelet-derived growth factor, transforming growth factor beta, and galectin-3. IL-34-Mu and M-CSF-Mu induce type I collagen synthesis by HSCs, the main collagen-producing cells in liver fibrosis. IL-13, whose expression correlates with the fibrosis stage in HCV-infected patients, decreases the expression of the collagenase, matrix metalloproteinase 1, by IL-34-Mu and M-CSF-Mu, thereby enhancing collagen synthesis. By inhibiting the production of interferon-gamma (IFN-c) by activated natural killer cells, IL34- Mu and M-CSF-Mu prevent the IFN-c-induced killing of HSCs. Conclusion: These results identify M-CSF and IL-34 as potent profibrotic factors in HCV liver fibrosis.