Cytokine expression in hepatocytes: Role of oxidant stress
Cytokine expression in hepatocytes: Role of oxidant stress
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DOI：
10.1089/jir.1998.18.629
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发表时间：
1998-08-01
影响因子：
2.3
通讯作者：
Luster, MI
中科院分区：
文献类型：
--
作者：
Dong, WM;Simeonova, PP;Luster, MI
炎症介质，包括细胞因子和趋化因子，与慢性肝病的病理学相关。人类的白细胞介素-8（IL-8）和啮齿类动物的巨噬细胞炎性蛋白-2（MIP-2），都是趋化因子C-X-C家族的成员，是特别有效的嗜中性粒细胞引诱剂，并且与慢性肝病有关。在肝脏中，细胞因子分泌通常与非实质细胞，特别是枯否细胞相关。在目前的研究中，趋化因子基因的表达和分泌进行了研究，在肝细胞与各种刺激。使用人Hep G2细胞，证明了与脂多糖（LPS）相反，肿瘤坏死因子-α（TNF-α）和H2 O2都是IL-8的有效诱导剂，推测通过蛋白激酶C（PKC）依赖性途径起作用。在用TNF-α、LPS和较小程度的H2 O2处理后，在新鲜分离的大鼠肝细胞中发生MIP-2表达。IL-8和MIP-2的分泌都被抗氧化剂如TMTU、DMSO、过氧化氢酶和N-乙酰半胱氨酸抑制，尽管程度不同。此外，体外TNF-α中和实验和用IL-8构建体转染Hep G2细胞证实TNF-α和H2 O2直接刺激IL-8分泌。RT-PCR分析表明，这些药物诱导的趋化因子分泌通过增加基因表达来进行。此外，发现多种细胞因子基因由肝细胞表达，包括MCP-1、烟碱诱导的中性粒细胞趋化因子（CINC）和IL-6。总之，这些研究表明肝细胞对生物学相关水平的常见活化剂（包括H2 O2）产生细胞因子和趋化因子，这些细胞因子和趋化因子有助于肝脏中的病理生理和修复过程。
Inflammatory mediators, including cytokines and chemokines, are associated with the pathology of chronic liver disease. Interleukin-8 (IL-8) in humans and macrophage inflammatory protein-2 (MIP-2) in rodents, both members of the C-X-C family of chemokines, are particularly potent neutrophil attractants and have been implicated in chronic liver diseases. In the liver, cytokine secretion is usually associated with nonparenchymal cells, particularly Kupffer cells. In the present studies, chemokine gene expression and secretion were investigated in hepatocytes treated with various stimulators. Using human Hep G2 cells, it was demonstrated that, in contrast to lipopolysaccharides (LPS), both tumor necrosis factor-alpha (TNF-alpha) and H2O2 are potent inducers of IL-8, presumably acting via protein kinase C (PKC)-dependent pathways. MIP-2 expression occurred in freshly isolated rat hepatocytes following treatment with TNF-alpha, LPS, and to a lesser degree, H2O2, Both IL-8 and MIP-2 secretion were inhibited, although to varying degrees, by such antioxidants as TMTU, DMSO, catalase, and N-acetylcysteine. Furthermore, in vitro TNF-alpha neutralization experiments and transfection of Hep G2 cells with an IL-8 construct confirmed that TNF-alpha and H2O2 directly stimulate IL-8 secretion. RT-PCR analyses indicated that chemokine secretion induced by these agents operates via increased gene expression. Furthermore, a variety of cytokine genes were found to be expressed by hepatocytes, including MCP-1, cytokine-induced neutrophil chemoattractant (CINC), and IL-6, Taken together, these studies indicate that hepatocytes respond to biologically relevant levels of common activators, including H2O2, to produce cytokines and chemokines that contribute to pathophysiologic and repair processes in the liver.