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Reduced Peripheral PGE2 Biosynthesis in Plasmodium falciparum Malaria Occurs through Hemozoin-Induced Suppression of Blood Mononuclear Cell Cyclooxygenase-2 Gene Expression via an Interleukin-10-Independent Mechanism

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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 E2 (PGE2) production are suppressed in children with falciparum malaria relative to healthy, malaria-exposed children with partial immunity. Furthermore, decreased COX-2/PGE2 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 PGE2 suppression, PBMCs were cultured from children with falciparum malaria. PGE2 production was suppressed under baseline and COX-2-promoting conditions (stimulation with lipopolysaccharide [LPS] and interferon [IFN]-γ) over prolonged periods, suggesting that an in vivo-derived product(s) was responsible for reduced PGE2 biosynthesis. Ingestion of hemozoin (malarial pigment) by PBMC was investigated as a source of COX-2/PGE2 suppression in PBMCs from healthy, malaria-naive adults. In addition, synthetically prepared hemozoin, β-hematin, was used to investigate the effects of the core iron component of hemozoin, ferriprotoporphyrin-IX (FPIX). Physiologic concentrations of hemozoin or β-hematin suppressed LPS- and IFN-γ-induced COX-2 mRNA in a time- and dose-dependent manner, resulting in decreased COX-2 protein and PGE2 production. Suppression of COX-2/PGE2 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/PGE2. Although hemozoin induced overproduction of IL-10, neutralizing IL-10 antibodies failed to restore PGE2 production. Thus, acquisition of hemozoin by blood mononuclear cells is responsible for suppression of PGE2 in malaria through inhibition of de novo COX-2 transcripts via molecular mechanisms independent of increased IL-10 production.

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Acknowledgments

We thank the staff members of the Albert Schweitzer Hospital in Lambaréné, Gabon, for their cooperation and technical assistance: Anita van den Biggelaar, Judith Jans, Hanna Knoop, Doris Luckner Barbara Moritz, Anselme Ndzengue, Marcel Nkeyi, Daniela Schmid, and Milena Sovric. Furthermore, we would like to thank Dr. Venkatachalam Udhayakumar for his scientific input.

This work was conducted at the University of Pittsburgh and was supported in part by the National Institutes of Health Grants AI-51305-01 (DJP) and AI-41764 (JBW), the VA Research Service (JBW), and the University of Pittsburgh Competitive Research Development Fund (DJP). Portions of this work were presented at The 51st Annual Meeting of the American Society of Tropical Medicine and Hygiene in Denver, CO, in November 2002. The title of the presentation was Cyclooxygenase-2 and Prostaglandin E2 Down-regulation by Hemozoin is Associated with Overproduction of TNF-α Implications for the Pathogenesis of Severe Malaria (abstract number 74).

The study was approved by the ethics committee of the International Foundation of the Albert Schweitzer Hospital, Duke University Medical Center Investigational Review Board, and the University of Pittsburgh Investigational Review Board, and informed consent was obtained from the participants or the parents of participating children.

There is no conflict of interest for any of the authors of the manuscript due to commercial or other affiliations.

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Authors and Affiliations

  1. Graduate School of Public Health, Department of Infectious Diseases and Microbiology, University of Pittsburgh, 130 DeSoto Street, 603 Parran Hall, Pittsburgh, Pennsylvania, 15261, USA

    Christopher C. Keller, Benjamin K. Nti & Douglas J. Perkins

  2. Department of Psychology, College of Charleston, Charleston, South Carolina, USA

    James B. Hittner

  3. Department of Medicine, VA and Duke University Medical Centers, Durham, North Carolina, USA

    J. Brice Weinberg

  4. Medical Research Unit, Albert Schweitzer Hospital, Lambaréné, Gabon

    Peter G. Kremsner

  5. Department of Parasitology, Institute for Tropical Medicine, University of Tübingen, Tübingen, Germany

    Peter G. Kremsner

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  1. Christopher C. Keller
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  2. James B. Hittner
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  3. Benjamin K. Nti
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  4. J. Brice Weinberg
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  5. Peter G. Kremsner
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  6. Douglas J. Perkins
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Correspondence to Douglas J. Perkins.

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Keller, C.C., Hittner, J.B., Nti, B.K. et al. Reduced Peripheral PGE2 Biosynthesis in Plasmodium falciparum Malaria Occurs through Hemozoin-Induced Suppression of Blood Mononuclear Cell Cyclooxygenase-2 Gene Expression via an Interleukin-10-Independent Mechanism. Mol Med 10, 45–54 (2004). https://doi.org/10.2119/2004-00035.Perkins

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