Abstract
Molecular immunologic determinants of disease severity during Plasmodium falciparum malaria are largely undetermined. Our recent investigations showed that peripheral blood mononuclear cell (PBMC) cyclooxygenase-2 (COX-2) gene expression and plasma prostaglandin E(2) (PGE(2)) production are suppressed in children with falciparum malaria relative to healthy, malaria-exposed children with partial immunity. Furthermore, decreased COX-2/PGE(2) levels were significantly associated with increased plasma interleukin-10 (IL-10), an anti-inflammatory cytokine that inhibits the expression of COX-2 gene products. To determine the mechanism(s) responsible for COX-2-derived PGE(2) suppression, PBMCs were cultured from children with falciparum malaria. PGE(2) production was suppressed under baseline and COX-2-promoting conditions (stimulation with lipopolysaccharide [LPS] and interferon [IFN]-gamma) over prolonged periods, suggesting that an in vivo-derived product(s) was responsible for reduced PGE(2) biosynthesis. Ingestion of hemozoin (malarial pigment) by PBMC was investigated as a source of COX-2/PGE(2) suppression in PBMCs from healthy, malaria-naive adults. In addition, synthetically prepared hemozoin, beta-hematin, was used to investigate the effects of the core iron component of hemozoin, ferriprotoporphyrin-IX (FPIX). Physiologic concentrations of hemozoin or b-hematin suppressed LPS- and IFN-gamma-induced COX-2 mRNA in a time- and dose-dependent manner, resulting in decreased COX-2 protein and PGE(2) production. Suppression of COX-2/PGE(2) by hemozoin was not due to decreased cell viability as evidenced by examination of mitochondrial bioactivity. These data illustrate that ingestion of FPIX by blood mononuclear cells is responsible for suppression of COX-2/PGE(2). Although hemozoin induced overproduction of IL-10, neutralizing IL-10 antibodies failed to restore PGE(2) production. Thus, acquisition of hemozoin by blood mononuclear cells is responsible for suppression of PGE(2) in malaria through inhibition of de novo COX-2 transcripts via molecular mechanisms independent of increased IL-10 production.
Highlights
The underlying pathophysiologic determinants of severe malaria are only partially defined, cytokines and effector molecules are important immunologic determinants for regulating disease susceptibility
prostaglandin E2 (PGE2) Production in Cultured peripheral blood mononuclear cell (PBMC) from Children with Malaria To determine if mononuclear phagocyte production of PGE2 is altered in children with falciparum malaria, PGE2 synthesis was determined in culture supernatants of PBMCs from healthy, malaria-exposed children and children with malaria
These results suggest that monocyte-derived PGE2 synthesis is significantly suppressed in children with malaria and is refractory to COX-2–promoting stimuli
Summary
The underlying pathophysiologic determinants of severe malaria are only partially defined, cytokines and effector molecules are important immunologic determinants for regulating disease susceptibility. Our recent investigations have focused on defining the role of prostaglandins as immunomodulatory factors in malaria. Eicosanoids, such as prostaglandin E2 (PGE2), regulate macrophage function, vascular permeability, extracellular adhesion molecules, fever, and cytokine production [1]. Our previous studies showed that plasma levels of PGE2 were significantly reduced in children with malaria and were significantly associated with increased plasma interleukin (IL)-10 levels [6]. Suppression of COX-2/PGE2 in our previous studies was associated with enhanced severity of falciparum malaria, the mechanism(s) for decreased PGE2 synthesis remain undefined.
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