Suppression of Prostaglandin E₂by Malaria Parasite Products and Antipyretics Promotes Overproduction of Tumor Necrosis Factor–α: Association with the Pathogenesis of Childhood Malarial Anemia

Abstract

Cytokines and effector molecules are important immunoregulatory molecules in human malaria. Tumor necrosis factor (TNF)-a limits malaria parasitemia but also promotes pathogenesis at high concentrations, whereas prostaglandin E 2 (PGE 2 ) inhibits TNF-a 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-a and PGE 2 are largely unexplored in human malaria, results presented here show that pfHz-induced suppression of PBMC COX-2 gene products induces overproduction of TNF-a. Moreover, addition of exogenous PGE 2 to pfHz-treated PBMCs dose-dependently decreased TNF-a production, whereas experimental COX inhibitors and antipyretics used during human malaria generated increased TNF-a production. Healthy, malariaexposed children had elevated levels of circulating bicyclo-PGE 2 /TNF-a, compared with children with malarial anemia ( ), with systemic bicyclo-PGE 2 and TNF-a significantly associated with hemoglobin concentrations P ! .01 ( ; ). The results of the present study illustrate that pfHz-induced suppression of PGE 2 promotes r p 0.745 P ! .01 overproduction of TNF-a, which is associated with enhanced malarial anemia.Malarial anemia (MA) is a multifaceted clinical manifestation of malaria that has varying etiologies, including intravascular and extravascular hemolysis of infected and noninfected red blood cells (RBCs), as well as suppression of erythropoiesis [1]. In Gabon, a hyperendemic Plasmodium falciparum malaria transmission area, the primary clinical manifestations of severe childhood malaria are severe anemia and/or hyperpar-

Increased circulating interleukin (IL)-23 in children with malarial anemia: In vivo and in vitro relationship with co-regulatory cytokines IL-12 and IL-10

“…Previous investigations from our laboratory illustrate that phagocytosis of malarial pigment (hemozoin, Hz) by cultured human peripheral blood mononuclear cells (PBMC) generates a profile of cytokine production similar to that observed in children with malarial anemia [27][28][29]. Hz is a Plasmodium-derived biomineralized product of heme, a prosthetic group of hemoglobin (Hb) liberated during Hb degradation [30].…”

“…A number of studies from our laboratory [27][28][29]38], as well as others [49][50][51], have shown that Hz is an important parasitic product that causes dysregulation of de novo cytokine production in human PBMC. As such, Hz was examined as a potential parasitic product that could alter the transcriptional expression of IL-23, IL-12, and IL-10.…”

“…We have previously shown that parasite-derived products, such as pfHz, cause dysregulation of de novo cytokine transcription in cultured PBMC [27][28][29]38]. IL-23 and IL-12 share the IL-12p40 subunit [17] and are both antagonized by IL-10 [22,23] and secreted forms of IL-12p40 [20,24].…”

Heme Impairs Prostaglandin E2 and TGF-β Production by Human Mononuclear Cells via Cu/Zn Superoxide Dismutase: Insight into the Pathogenesis of Severe Malaria

“…Moreover, a crystal form of heme molecules produced by Plasmodium sp., and referred to as hemozoin, also acts as a proinflammatory agonist and thus could be associated with the development of severe forms of malaria (16)(17)(18). Hemozoin inhibits PGE 2 production in both mice (19) and humans (20,21), and there is an inverse relationship between PGE 2 and blood mononuclear cell cyclooxygenase-2 with disease severity in children with P. falciparum malaria (22). Until now there is no clear description of the effect of free heme on the PGE 2 production.…”

Moving toward hematological predictors of disease severity in malaria: Going with the flow

“…Likewise, as antiretroviral therapy is increasingly available in sub-Saharan Africa; future studies among such children would be needed. It is noteworthy that the role of hemozoin in malaria pathogenesis, including PCM, has been extensively studied [15][16][17]. A recent multisite study of 26,000 pediatric malaria cases in sub-Saharan Africa concluded that PCM, while predictive of severe disease and mortality, failed to provide additional prognostic value beyond conventional markers of disease severity [18].…”