Viral and host factors induce macrophage activation and loss of toll-like receptor tolerance in chronic HCV infection
Viral and host factors induce macrophage activation and loss of toll-like receptor tolerance in chronic HCV infection
复制标题
DOI：
10.1053/j.gastro.2007.08.003
复制
发表时间：
2007-11-01
期刊：
影响因子：
29.4
通讯作者：
Szabo, Gyongyi
中科院分区：
文献类型：
--
作者：
Dolganiuc, Angela;Norkina, Oxana;Szabo, Gyongyi
背景与目的：慢性丙型肝炎病毒（cHCV）感染的持续性炎症有助于肝损伤的进展。重复暴露于Toll样受体（TLR）配体导致耐受性，这是一种旨在限制炎症的保护机制。方法：单核细胞/巨噬细胞反复刺激通过促炎烟碱诱导TLR和活化标志物进行评价。结果如下：与对照组或非酒精性脂肪性肝炎患者的单核细胞不同，cHCV患者的单核细胞是高反应性的，并且没有显示出对TLR配体的同源或异源耐受性，表现为肿瘤坏死因子（TNF）-α产生升高。cHCV患者血清干扰素（IFN）-γ、内毒素（TLR 4配体）和HCV核心蛋白（TLR 2配体）水平升高，提示体内单核细胞预激活的潜在机制。用IFN-γ处理正常单核细胞导致对脂多糖（LPs）或HCV核心蛋白的耐受性丧失。此外，我们发现在cHCV患者的单核细胞和在IFN-γ + LPS预处理后失去TLR耐受性的正常单核细胞中，MyD 88-IRAK 1复合物和核因子（NF）-κ B活性的水平增加。TLR非耐受性cHCV单核细胞体外分化为巨噬细胞恢复了它们表现出对LPS和HCV核心蛋白的TLR耐受性的能力，并且这可以通过施用IFN-γ逆转。cHCV患者在循环和肝脏中表现出增加的TNF-α。在cHCV肝脏中，我们发现库普弗细胞/巨噬细胞活化，表现为CD 163和CD 33表达增加。结论：我们发现，宿主衍生因子（IFN-γ和内毒素）和病毒因子（HCV核心蛋白）协同作用，诱导和维持单核细胞/巨噬细胞活化，从而有利于cHCV感染患者的持续炎症。
Background & Aims: Persistent inflammation contributes to progression of liver damage in chronic HCV (cHCV) infection. Repeated exposure to toll-like receptor (TLR) ligands results in tolerance, a protective mechanism aimed at limiting inflammation. Methods: Monocytes/macrophages were repeatedly stimulated via proinflammatory cytokine-inducing TLRs and evaluated for activation markers. Results: Unlike monocytes of controls or patients with nonalcoholic steatohepatitis, the monocytes of cHCV patients were hyperresponsive and failed to show homo- or heterotolerance to TLR ligands, manifested by elevated tumor necrosis factor (TNF)-alpha production. Serum levels of interferon (IFN)-gamma, endotoxin (TLR4 ligand), and HCV core protein (TLR2 ligand) were elevated in cHCV patients suggesting potential mechanisms for in vivo monocyte preactivation. Treatment of normal monocytes with IFN-gamma resulted in loss of tolerance to lipopolysaccharide (LPs) or HCV core protein. Furthermore, we found increased levels of MyD88-IRAK1 complexes and nuclear factor (NF)-kappa B activity both in monocytes of cHCV patients and in normal monocytes that lost TLR tolerance after IFN-gamma + LPS pretreatment. In vitro differentiation of TLR non-tolerant cHCV monocytes into macrophages restored their capacity to exhibit TLR tolerance to LPS and HCV core protein, and this could be reversed by administration of IFN-gamma. cHCV patients exhibited increased TNF-alpha in the circulation and in the liver. In cHCV livers, we found Kupffer cell/macrophage activation indicated by increased CD163 and CD33 expression. Conclusions: We identified that host-derived factors (IFN-gamma and endotoxin) and viral factors (HCV core protein) act in tandem to induce and maintain monocyte/macrophage activation, thus favoring persistent inflammation in patients with cHCV infection.