title: 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.
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.
authors.affiliation: Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto Street, Pittsburgh, PA 15261, USA.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Keller
authors.forename: James B
authors.initials: JB
authors.lastname: Hittner
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Nti
authors.forename: J Brice
authors.initials: JB
authors.lastname: Weinberg
authors.forename: Peter G
authors.initials: PG
authors.lastname: Kremsner
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Perkins
mesh_terms: D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000097:blood / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006420:Hemeproteins / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma; D016753:Interleukin-10 / Q000096:biosynthesis / Q000097:blood; D007963:Leukocytes, Mononuclear / Q000201:enzymology / Q000378:metabolism*; D008070:Lipopolysaccharides; D016778:Malaria, Falciparum / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis
chemical_list: D006420:Hemeproteins; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D012333:RNA, Messenger; D016753:Interleukin-10; C020753:hemozoin; D007371:Interferon-gamma; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone