Keller Christopher C, Davenport Gregory C, Dickman Katherine R, Hittner James B, Kaplan Sandra S, Weinberg J Brice, Kremsner Peter G, Perkins Douglas J
Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA, and Albert Schweitzer Hospital, Lambaréné, Gabon.
J Infect Dis. 2006 May 15;193(10):1384-93. doi: 10.1086/503047. Epub 2006 Apr 7.
Cytokines and effector molecules are important immunoregulatory molecules in human malaria. Tumor necrosis factor (TNF)-alpha limits malaria parasitemia but also promotes pathogenesis at high concentrations, whereas prostaglandin E2 (PGE2) inhibits TNF-alpha production and is reduced in childhood malaria, at least in part, through suppression of cyclooxygenase (COX)-2 following the ingestion of Plasmodium falciparum hemozoin (pfHz; malarial pigment) by peripheral blood mononuclear cells (PBMCs). Although molecular interactions between TNF-alpha and PGE2 are largely unexplored in human malaria, results presented here show that pfHz-induced suppression of PBMC COX-2 gene products induces overproduction of TNF-alpha. Moreover, addition of exogenous PGE2 to pfHz-treated PBMCs dose-dependently decreased TNF-alpha production, whereas experimental COX inhibitors and antipyretics used during human malaria generated increased TNF-alpha production. Healthy, malaria-exposed children had elevated levels of circulating bicyclo-PGE2/TNF-alpha, compared with children with malarial anemia (P<.01), with systemic bicyclo-PGE2 and TNF-alpha significantly associated with hemoglobin concentrations (r=0.745; P<.01). The results of the present study illustrate that pfHz-induced suppression of PGE2 promotes overproduction of TNF-alpha, which is associated with enhanced malarial anemia.
细胞因子和效应分子是人类疟疾中重要的免疫调节分子。肿瘤坏死因子（TNF）-α可限制疟疾寄生虫血症，但在高浓度时也会促进发病机制，而前列腺素E2（PGE2）可抑制TNF-α的产生，并且在儿童疟疾中减少，至少部分是通过外周血单核细胞（PBMC）摄取恶性疟原虫血色素（pfHz；疟色素）后抑制环氧化酶（COX）-2来实现的。尽管在人类疟疾中TNF-α与PGE2之间的分子相互作用在很大程度上尚未得到探索，但此处呈现的结果表明，pfHz诱导的PBMC COX-2基因产物抑制会导致TNF-α的过量产生。此外，向pfHz处理的PBMC中添加外源性PGE2可剂量依赖性地降低TNF-α的产生，而人类疟疾期间使用的实验性COX抑制剂和解热药会导致TNF-α产生增加。与患有疟疾贫血的儿童相比，健康的、接触过疟疾的儿童循环双环PGE2/TNF-α水平升高（P<0.01），全身双环PGE2和TNF-α与血红蛋白浓度显著相关（r = 0.745；P<0.01）。本研究结果表明，pfHz诱导的PGE2抑制会促进TNF-α的过量产生，这与疟疾贫血的加重有关。
