title: Tumor necrosis factor reduces Plasmodium falciparum growth and activates calcium signaling in human malaria parasites.
abstract: BACKGROUND
  Plasmodium has a complex biology including the ability to interact with host signals modulating their function through cellular machinery. Tumor necrosis factor (TNF) elicits diverse cellular responses including effects in malarial pathology and increased infected erythrocyte cytoadherence. As TNF levels are raised during Plasmodium falciparum infection we have investigated whether it has an effect on the parasite asexual stage.
  
  
  METHODS
  Flow cytometry, spectrofluorimetric determinations, confocal microscopy and PCR real time quantifications were employed for characterizing TNF induced effects and membrane integrity verified by wheat germ agglutinin staining.
  
  
  RESULTS
  TNF is able to decrease intracellular parasitemia, involving calcium as a second messenger of the pathway. Parasites incubated for 48 h with TNF showed reduced erythrocyte invasion. Thus, TNF induced rises in intracellular calcium concentration, which were blocked by prior addition of the purinergic receptor agonists KN62 and A438079, or interfering with intra- or extracellular calcium release by thapsigargin or EGTA (ethylene glycol tetraacetic acid). Importantly, expression of PfPCNA1 which encodes the Plasmodium falciparum Proliferating-Cell Nuclear Antigen 1, decreased after P. falciparum treatment of TNF (tumor necrosis factor) or 6-Bnz cAMP (N(6)-benzoyladenosine-3',5'-cyclic monophosphate sodium salt).
  
  
  CONCLUSIONS
  This is potentially interesting data showing the relevance of calcium in downregulating a gene involved in cellular proliferation, triggered by TNF.
  
  
  CONCLUSIONS
  The data show that Plasmodium may subvert the immunological system and use TNF for the control of its proliferation within the vertebrate host.
authors.affiliation: Department of Physiology, Instituto de Biociências, Universidade de São Paulo, Rua do Matão, travessa 14, n321, CEP 05508-900 São Paulo, SP, Brazil.
authors.forename: Laura N
authors.initials: LN
authors.lastname: Cruz
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Biochemistry, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil.
authors.forename: Henning
authors.initials: H
authors.lastname: Ulrich
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
authors.forename: Alister G
authors.initials: AG
authors.lastname: Craig
authors.affiliation: Department of Physiology, Instituto de Biociências, Universidade de São Paulo, Rua do Matão, travessa 14, n321, CEP 05508-900 São Paulo, SP, Brazil. Electronic address: cgarcia@usp.br.
authors.forename: Célia R S
authors.initials: CR
authors.lastname: Garcia
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects*; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology; D004912:Erythrocytes / Q000469:parasitology*; D006790:Host-Parasite Interactions; D006801:Humans; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development / Q000276:immunology / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D015800:Protozoan Proteins / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D018809:Proliferating Cell Nuclear Antigen; D015800:Protozoan Proteins; D014409:Tumor Necrosis Factor-alpha
keywords: Calcium signaling; Cytoadhesion; Malaria; Plasmodium falciparum; Proliferating cell nuclear antigen-1; Tumor necrosis factor