Xiong Shigang, She Hongyun, Sung Chin K, Tsukamoto Hidekazu
Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
Alcohol. 2003 Jun;30(2):107-13. doi: 10.1016/s0741-8329(03)00100-9.
Alcoholic liver disease is associated with hepatic iron accumulation, and iron supplementation exacerbates alcoholic liver disease, suggesting the pathogenic role of iron in alcoholic liver disease. We have tested a hypothesis that iron plays a signaling role in activation of redox-sensitive nuclear factor-kappa B (NF-kappaB) and that increased iron content results in heightened expression of proinflammatory cytokines in Kupffer cells because of this signaling. In cultured Kupffer cells isolated from normal rats, treatment with a lipophilic iron chelator, 1,2-dimethyl-3-hydroxypyrid-4-one (L1), markedly reduced lipopolysaccharide (LPS)-induced NF-kappaB activation and expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6. Kupffer cells, isolated from rats with experimentally induced alcoholic liver disease, had significant increases in nonheme iron content, NF-kappaB binding, and mRNA expression for TNF-alpha and macrophage inflammatory protein-1. Ex vivo L1 treatment normalized all these parameters. Addition of ferrous iron to cultured normal rat Kupffer cells increased I-kappa B kinase (IKK) activity at 15 min and NF-kappaB binding at 30 min. L1 pretreatment completely abrogated both effects. Moreover, the iron treatment increased TNF-alpha release and TNF-alpha promoter activity in a NF-kappaB-dependent manner. Ferrous iron also transiently decreased cytoplasmic I-kappa B-alpha (IkappaB-alpha), with concomitant increases in nuclear p65 protein and DNA binding of p65/p50. Taken together, these results support the existence of iron-dependent signaling for activation of IKK/NF-kappaB in Kupffer cells, and this iron signaling serves as a target for a potential priming effect for the pathogenesis of experimental alcoholic liver disease.
酒精性肝病与肝脏铁蓄积有关，补充铁会加重酒精性肝病，提示铁在酒精性肝病中具有致病作用。我们检验了一个假说，即铁在氧化还原敏感的核因子-κB（NF-κB）激活中起信号传导作用，并且由于这种信号传导，铁含量增加会导致库普弗细胞中促炎细胞因子的表达升高。在从正常大鼠分离的培养库普弗细胞中，用亲脂性铁螯合剂1,2-二甲基-3-羟基吡啶-4-酮（L1）处理可显著降低脂多糖（LPS）诱导的NF-κB激活以及肿瘤坏死因子-α（TNF-α）和白细胞介素-6的表达。从实验性诱导酒精性肝病的大鼠分离的库普弗细胞，其非血红素铁含量、NF-κB结合以及TNF-α和巨噬细胞炎性蛋白-1的mRNA表达均显著增加。离体L1处理使所有这些参数恢复正常。向培养的正常大鼠库普弗细胞中添加亚铁在15分钟时增加I-κB激酶（IKK）活性，在30分钟时增加NF-κB结合。L1预处理完全消除了这两种作用。此外，铁处理以NF-κB依赖的方式增加TNF-α释放和TNF-α启动子活性。亚铁还短暂降低细胞质I-κB-α（IkappaB-α），同时核p65蛋白和p65/p50的DNA结合增加。综上所述，这些结果支持在库普弗细胞中存在铁依赖性信号传导以激活IKK/NF-κB，并且这种铁信号传导是实验性酒精性肝病发病机制潜在启动效应的靶点。
