Control of intracellular signaling responsible for oxidative stress in blood cells

众所周知，骨髓细胞对外源性物质诱导的氧化应激敏感。然而，控制血细胞易感性的分子机制知之甚少。本研究的目的是证明应激蛋白是否参与骨髓来源细胞对氧化应激的易感性。有毒的苯代谢物，如氢醌和苯醌，在几种白血病细胞系中诱导细胞死亡，与非血细胞相比，血细胞祖细胞和小鼠骨髓细胞的模型在显著较低的浓度下，如HepG 2肝癌和WI-38成纤维细胞。这些氧化剂在血细胞中诱导血红素加氧酶-1（HO-1）和NAD（P）H-醌氧化还原酶1，这是典型的应激蛋白，可减少应激诱导的细胞损伤，但程度远低于非血细胞。在血细胞模型中，Nrf 2（一种在应激蛋白基因表达中起核心作用的转录因子）的功能以及靶向顺式调节元件抗氧化反应元件（ARE）的反应受损。这些结果表明，血细胞对苯代谢物的易感性部分是由于Nrf 2-ARE信号通路受损引起的应激蛋白反应受限。我们进一步研究了氧化应激是否参与5-FU介导的骨髓毒性。5-FU在体内外均可增加骨髓细胞HO-1蛋白的表达。5-FU刺激骨髓细胞产生活性氧。此外，5-FU介导的HO-1诱导和骨髓毒性以平行方式发生。这些结果表明，氧化应激部分参与5-FU引起的骨髓毒性。

It has been well known that bone marrow cells are susceptible to xenobiotic-induced oxidative stress. However, molecular mechanisms that governed susceptibility of blood cells are poorly understood. Aim of the present study was to demonstrate whether responsibilities of the stress proteins are involved in the susceptibility to oxidative stress in bone marrow derived cells.Toxic benzene metabolites, such as hydroquinone and benzoquinone, induced cell death at significantly lower concentrations in several leukemia cell lines, a model of blood cell progenitors as well as mouse bone marrow cells as compared to non-blood cells, such as HepG2 hepatoma and WI-38 fibroblast cells. These oxidants induced heme oxygenase-1 (H0-1) and NAD(P)H-quinone oxidoreductase 1, typical stress proteins which diminish stress-induced cell damage, in the blood cells but to a far lesser extent than in the non-blood cells. Functions of Nrf2, a transcription factor that bares a central role in gene expressions of the stress proteins, and responses of the target cis-regulatory element, antioxidant responsive element (ARE), were impaired in the blood cell models. These results suggest that susceptibility of blood cells to benzene metabolites is partly due to the restricted response of the stress proteins caused by the impaired Nrf2-ARE signaling.We have further examined whether oxidative stress is involved in 5-fluorouracil (5-FU)-mediated myelotoxicity. 5-FU increased HO-1 protein in bone marrow cells in vitro as well as in vivo. 5-FU stimulated production of reactive oxygen species in bone marrow cells. Furthermore, 5-FU-mediated HO-1 induction and myelotoxicity occurred in a parallel fashion. These results suggest that oxidative stress is partly involved in myelotoxicity caused by 5-FU.