Inhibition of proteasome function leads to NF-κB-independent IL-8 expression in human hepatocytes
Inhibition of proteasome function leads to NF-κB-independent IL-8 expression in human hepatocytes
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DOI：
10.1053/jhep.2003.50470
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发表时间：
2003-11-01
期刊：
影响因子：
13.5
通讯作者：
McClain, CJ
中科院分区：
文献类型：
--
作者：
Joshi-Barve, S;Barve, SS;McClain, CJ
细胞蛋白质的分解是一个高度调节的过程，而泛素-蛋白酶体途径是细胞中主要的蛋白水解系统。它调节许多蛋白质的水平，这些蛋白质控制基因表达和细胞分裂，以及对压力和炎症的反应。最近的研究报道了酒精性肝病（AID）中蛋白酶体功能的异常。此外，在ALD的实验模型中，蛋白酶体功能受损与氧化应激之间有直接关系。中性粒细胞浸润是ALD的标志，并且活化的中性粒细胞被认为在ALD的病理学中起作用。白细胞介素8（IL-8）作为一种强有力的中性粒细胞趋化因子和激活剂，可能在多种形式的肝损伤中发挥关键的机制作用。在这项研究中，我们评估了抑制蛋白酶体功能对人胎肝细胞和肝癌细胞表达和释放IL-8的影响。我们的数据表明，肝细胞中蛋白酶体功能的抑制导致凋亡性细胞死亡。肝细胞存活率降低与IL-8在蛋白质和信使RNA（mRNA）水平上的表达增强一致。IL-8的这种增加不依赖于核因子κ B（NF-κ B）的激活，并与c-Jun N-末端激酶（JNK）和激活蛋白-1（AP-1）活性的增加相关。总之，由于蛋白酶体功能抑制而死亡的肝细胞产生大量促炎趋化因子IL-8，可能导致中性粒细胞浸润、炎症增加和肝损伤。
Breakdown of cellular proteins is a highly regulated process, and the ubiquitin-proteasome pathway is the major proteolytic system in the cell. It regulates the levels of numerous proteins that control gene expression and cell division, as well as responses to stress and inflammation. Recent studies have reported abnormalities in proteasome function in alcoholic liver disease (AID). Moreover, a direct relation has been reported between impaired proteasome function and oxidative stress in experimental models of ALD. Neutrophil infiltration is a hallmark of ALD, and activated neutrophils are thought to play a role in the pathology of ALD. As a potent neutrophil chemoattractant and activator, interleukin 8 (IL-8) likely plays a key mechanistic role in many forms of liver injury. In this study, we evaluated the effects of inhibition of proteasome function on expression and release of IL-8 by human fetal hepatocytes and hepatoma cells. Our data demonstrate that inhibition of proteasome function in hepatocytes leads to apoptotic cell death. Decreased hepatocyte survival coincides with enhanced expression of IL-8, both at the protein and the messenger RNA (mRNA) levels. This increase in IL-8 is independent of nuclear factor kappaB (NF-kappaB) activation and is associated with an increase in c-Jun N-terminal kinase (JNK) and activator protein-1 (AP-1) activity. In conclusion, hepatocytes dying because of inhibition of proteasome function produce massive quantities of the proinflammatory chemokine IL-8, possibly resulting in neutrophil infiltration, increased inflammation, and liver injury.