Suppression of prostaglandin E2 by malaria parasite products and antipyretics promotes overproduction of tumor necrosis factor-alpha: association with the pathogenesis of childhood malarial anemia.
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.
Keller
Christopher C
CC
Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA, and Albert Schweitzer Hospital, Lambaréné, Gabon.
Davenport
Gregory C
GC
Dickman
Katherine R
KR
Hittner
James B
JB
Kaplan
Sandra S
SS
Weinberg
J Brice
JB
Kremsner
Peter G
PG
Perkins
Douglas J
DJ
D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000494:pharmacology; D000740:Anemia / Q000188:drug therapy / Q000276:immunology*; D000818:Animals; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D051546:Cyclooxygenase 2 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000097:blood / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006420:Hemeproteins / Q000494:pharmacology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008137:Longitudinal Studies; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000276:immunology*; D008297:Male; D010587:Phagocytosis; D010963:Plasmodium falciparum / Q000378:metabolism; D011446:Prospective Studies; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D018712:Analgesics, Non-Narcotic; D006420:Hemeproteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C020753:hemozoin; D051546:Cyclooxygenase 2; D015232:Dinoprostone