Heme Impairs Prostaglandin E2 and TGF-β Production by Human Mononuclear Cells via Cu/Zn Superoxide Dismutase: Insight into the Pathogenesis of Severe Malaria
Heme Impairs Prostaglandin E2 and TGF-β Production by Human Mononuclear Cells via Cu/Zn Superoxide Dismutase: Insight into the Pathogenesis of Severe Malaria
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DOI：
10.4049/jimmunol.0904179
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发表时间：
2010-07-15
影响因子：
4.4
通讯作者：
Barral-Netto, Manoel
中科院分区：
文献类型：
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作者：
Andrade, Bruno B.;Araujo-Santos, Theo;Barral-Netto, Manoel
在许多溶血性疾病中，例如疟疾，游离血红素的释放参与了氧化应激和组织损伤的触发。患有严重疟疾的患者通常具有受损的调节反应。虽然有趣，但很少有关于血红素参与免疫反应调节的数据。在这项研究中，我们调查了人间日疟中游离血红素与抗炎介质如PGE（2）和TGF-β抑制的关系。与轻度疾病患者相比，重度疾病患者的溶血率较高，血浆Cu/Zn超氧化物歧化酶（SOD-1）浓度较高，PGE（2）和TGF-β浓度较低。此外，SOD-1浓度与血浆TNF-α水平呈正相关。在抗疟治疗过程中，重症患者血浆SOD-1浓度降低，而PGE（2）和TGF-β浓度升高。使用人单核细胞的体外模型，我们证明了血红素对PGE（2）和TGF-β产生的损害作用部分涉及血红素与CD 14的结合，并依赖于SOD-1的产生。除了进一步了解间日疟的发病机制，目前的结果可能代表了溶血性疾病的一般机制，并可能是有用的治疗方法的未来研究。免疫学杂志，2010，185：1196-1204。
In many hemolytic disorders, such as malaria, the release of free heme has been involved in the triggering of oxidative stress and tissue damage. Patients presenting with severe forms of malaria commonly have impaired regulatory responses. Although intriguing, there is scarce data about the involvement of heme on the regulation of immune responses. In this study, we investigated the relation of free heme and the suppression of anti-inflammatory mediators such as PGE(2) and TGF-beta in human vivax malaria. Patients with severe disease presented higher hemolysis and higher plasma concentrations of Cu/Zn superoxide dismutase (SOD-1) and lower concentrations of PGE(2) and TGF-beta than those with mild disease. In addition, there was a positive correlation between SOD-1 concentrations and plasma levels of TNF-alpha. During antimalaria treatment, the concentrations of plasma SOD-1 reduced whereas PGE(2) and TGF-beta increased in the individuals severely ill. Using an in vitro model with human mononuclear cells, we demonstrated that the heme effect on the impairment of the production of PGE(2) and TGF-beta partially involves heme binding to CD14 and depends on the production of SOD-1. Aside from furthering the current knowledge about the pathogenesis of vivax malaria, the present results may represent a general mechanism for hemolytic diseases and could be useful for future studies of therapeutic approaches. The Journal of Immunology, 2010, 185: 1196-1204.