LPS stimulation during HCV infection induces MMP/TIMP1 imbalance in macrophages
LPS stimulation during HCV infection induces MMP/TIMP1 imbalance in macrophages
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HCV感染期间LPS刺激引起巨噬细胞中MMP/TIMP1失衡
DOI：
10.1099/jmm.0.001185
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发表时间：
2020-01-01
影响因子：
3
通讯作者：
Wang, Yili
中科院分区：
文献类型：
--
作者：
Fan, Chao;Zhang, Xiaoxiao;Wang, Yili
导论.在慢性丙型肝炎病毒（HCV）感染期间，HCV抗原建立内毒素的交叉耐受性，但在这种情况下的额外脂多糖（LPS）刺激作用知之甚少。瞄准本研究旨在探讨慢性丙型肝炎感染时上调的LPS对MMP和TIMP表达的影响。方法论在本研究中，我们分析了HCV抗原和LPS刺激对外周血单个核细胞（PBMC）在体内和体外的影响。从HCV患者中分离出巨噬细胞，并检查它们与内毒素耐受性的关系。分析巨噬细胞中MMP/TIMP 1的表达及其相关信号通路。采用巨噬细胞与Huh 7.5细胞共培养模型，分析交叉耐受对Ⅰ型胶原沉积的影响。结果发现HCV患者的LPS水平显著较高，特别是在HCV诱导的肝纤维化患者中。此外，虽然患者血清LPS水平偶尔上调，但由于内毒素交叉耐受，它不会诱导PBMC产生强烈的免疫应答，这是根据IL-6和TNF-α水平的变化来测量的。然而，TIMP1表达在刺激期间显著增加，表现出耐受/抗性表型，这与巨噬细胞中的TGF-β/Erk活化相关。然而，MMP水平并没有由于内毒素耐受而增加，这最终导致MMP/TIMP失衡并影响I型胶原的沉积。结论在HCV抗原诱导的内毒素交叉耐受期间增加的LPS刺激巨噬细胞有助于MMP/TIMP 1失衡和胶原I沉积。
Introduction. During chronic hepatitis C virus (HCV) infections, HCV antigens establish cross-tolerance of endotoxins, but additional lipopolysaccharide (LPS) stimulation effects in this condition are poorly understood. Aim. This study aims to investigate the effects of the upregulated LPS on MMP and TIMP expression during chronic hepatitis C infection. Methodology. In the present study, we analysed the effect of HCV antigens and LPS stimulation on peripheral blood mononuclear cells (PBMCs) both in vivo and in vitro. Macrophages from HCV patients were isolated and their association with endotoxin tolerance was examined. MMP/TIMP1 expression and the related signalling pathways in macrophages were analysed. The macrophage and Huh7.5 cell co-culture model was used to analyse the effects of the cross-tolerance on collagen I deposition. Results. LPS levels were found to be significantly higher in HCV patients, particularly in those with HCV-induced liver fibrosis. In addition, although LPS serum level was occasionally upregulated in the patients, it did not induce intense immune response in PBMCs due to endotoxin cross-tolerance, and this was measured according to the changes in IL-6 and TNF-α levels. However, TIMP1 expression increased significantly during stimulation, exhibiting a tolerance/resistance phenotype, which was associated with TGF-β/Erk activation in macrophages. However, MMP levels did not increase due to endotoxin tolerance, which ultimately led to MMP/TIMP imbalance and influenced the deposition of collagen I. Conclusion. Increased LPS stimulation of macrophage during HCV antigen-induced endotoxin cross-tolerance contributes to MMP/TIMP1 imbalance and collagen I deposition.