Macrophage Preconditioning with Synthetic Malaria Pigment Reduces Cytokine Production via Heme Iron-Dependent Oxidative Stress-猫眼课题宝

用合成疟疾色素预处理巨噬细胞通过血红素铁依赖性氧化应激减少细胞因子的产生

DOI：

发表时间：

2000

期刊：

Laboratory Investigation

影响因子：

通讯作者：

中科院分区：

医学2区

文献类型：

作者：

D. Taramelli;S. Recalcati;N. Basilico;P. Olliaro;G. Cairo

疟原虫色素（疟原虫色素）是一种血红素（亚铁原卟啉IX）的聚合物，来源于红细胞内疟原虫摄取的血红蛋白，调节吞噬细胞产生的细胞因子。用合成的β-正铁血红素（BH）（结构上与天然疟原虫色素相同）喂养小鼠腹腔巨噬细胞（PM），在对脂多糖（LPS）的反应中不再产生肿瘤坏死因子α（TNFα）和一氧化氮（NO）。NO合成的损害是由于诱导型一氧化氮合酶（iNOS）产生的抑制。BH介导的PM功能的抑制不能归因于BH的铁释放，因为既没有铁螯合剂的预防，也没有检测到铁调节蛋白活性的下调。抑制似乎与色素诱导的氧化应激有关，因为（a）硫醇化合物部分恢复PM功能，（B）血红素加氧酶（HO-1）和过氧化氢酶mRNA水平上调，（c）BH处理的细胞中自由基产生增加。细胞的抗氧化防御决定了对BH的反应：小胶质细胞显示出较低程度的HO-1和过氧化氢酶mRNA的诱导和较低程度的氧自由基积累，对BH对细胞因子产生的抑制作用不太敏感。结果表明，BH是耐降解HO-1和血红素铁介导的氧化应激可能有助于疟疾诱导的免疫抑制。这项研究可能有助于关联疟疾的不同临床表现，从简单到严重的疾病，与吞噬细胞功能失调，并促进更好的治疗策略，以抵消疟原虫色素积累的影响。

Hemozoin (malaria pigment), a polymer of hematin (ferri-protoporphyrin IX) derived from hemoglobin ingested by intraerythrocytic plasmodia, modulates cytokine production by phagocytes. Mouse peritoneal macrophages (PM) fed with synthetic β-hematin (BH), structurally identical to native hemozoin, no longer produce tumor necrosis factor α (TNFα) and nitric oxide (NO) in response to lipopolysaccharide (LPS). Impairment of NO synthesis is due to inhibition of inducible nitric oxide synthase (iNOS) production. BH-mediated inhibition of PM functions cannot be ascribed to iron release from BH because neither prevention by iron chelators nor down-regulation of iron-regulatory protein activity was detected. Inhibition appears to be related to pigment-induced oxidative stress because (a) thiol compounds partially restored PM functions, (b) heme oxygenase (HO-1) and catalase mRNA levels were up-regulated, and (c) free radicals production increased in BH-treated cells. The antioxidant defenses of the cells determine the response to BH: microglia cells, which show a lower extent of induction of HO-1 and catalase mRNAs and lower accumulation of oxygen radicals, are less sensitive to the inhibitory effect of BH on cytokine production. Results indicate that BH is resistant to degradation by HO-1 and that heme-iron mediated oxidative stress may contribute to malaria-induced immunosuppression. This study may help correlate the different clinical manifestations of malaria, ranging from uncomplicated to severe disease, with dysregulation of phagocyte functions and promote better therapeutic strategies to counteract the effects of hemozoin accumulation.