title: Endothelial cells potentiate interferon-γ production in a novel tripartite culture model of human cerebral malaria.
abstract: We have established a novel in vitro co-culture system of human brain endothelial cells (HBEC), Plasmodium falciparum parasitised red blood cells (iRBC) and peripheral blood mononuclear cells (PBMC), in order to simulate the chief pathophysiological lesion in cerebral malaria (CM). This approach has revealed a previously unsuspected pro-inflammatory role of the endothelial cell through potentiating the production of interferon (IFN)-γ by PBMC and concurrent reduction of interleukin (IL)-10. The IFN-γ increased the expression of CXCL10 and intercellular adhesion molecule (ICAM)-1, both of which have been shown to be crucial in the pathogenesis of CM. There was a shift in the ratio of IL-10:IFN-γ protein from >1 to <1 in the presence of HBEC, associated with the pro-inflammatory process in this model. For this to occur, a direct contact between PBMC and HBEC, but not PBMC and iRBC, was necessary. These results support HBEC playing an active role in the pathogenesis of CM. Thus, if these findings reflect the pathogenesis of CM, inhibition of HBEC and PBMC interactions might reduce the occurrence, or improve the prognosis, of the condition.
authors.affiliation: School of Medical Sciences and Bosch Institute, University of Sydney, Sydney, Australia.
authors.forename: Loke Tim
authors.initials: LT
authors.lastname: Khaw
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Ball
authors.forename: Jacob
authors.initials: J
authors.lastname: Golenser
authors.forename: Valery
authors.initials: V
authors.lastname: Combes
authors.forename: Georges E
authors.initials: GE
authors.lastname: Grau
authors.forename: Julie
authors.initials: J
authors.lastname: Wheway
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Mitchell
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Hunt
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D018929:Cell Culture Techniques; D054357:Chemokine CXCL10 / Q000378:metabolism; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology / Q000469:parasitology; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D007155:Immunologic Factors / Q000378:metabolism; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis; D007376:Interleukin-2 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism; D016779:Malaria, Cerebral / Q000276:immunology* / Q000469:parasitology / Q000473:pathology*; D008954:Models, Biological; D010271:Parasites / Q000187:drug effects / Q000502:physiology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000502:physiology
chemical_list: D057134:Antibodies, Neutralizing; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C114753:CXCL10 protein, human; D061945:Caspase Inhibitors; D054357:Chemokine CXCL10; D000949:Histocompatibility Antigens Class II; C498514:ICOSLG protein, human; D007155:Immunologic Factors; D060945:Inducible T-Cell Co-Stimulator Ligand; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D007376:Interleukin-2; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10; D007371:Interferon-gamma; D020170:Caspase 1