title: Direct activation of human endothelial cells by Plasmodium falciparum-infected erythrocytes.
abstract: Cytoadherence of Plasmodium falciparum-infected erythrocytes (PRBC) to endothelial cells causes severe clinical disease, presumably as a of result perfusion failure and tissue hypoxia. Cytoadherence to endothelial cells is increased by endothelial cell activation, which is believed to occur in a paracrine fashion by mediators such as tumor necrosis factor alpha (TNF-alpha) released from macrophages that initially recognize PRBC. Here we provide evidence that PRBC directly stimulate human endothelial cells in the absence of macrophages, leading to increased expression of adhesion-promoting molecules, such as intercellular adhesion molecule 1. Endothelial cell stimulation by PRBC required direct physical contact for a short time (30 to 60 min) and was correlated with parasitemia. Gene expression profiling of endothelial cells stimulated by PRBC revealed increased expression levels of chemokine and adhesion molecule genes. PRBC-stimulated endothelial cells especially showed increased expression of molecules involved in parasite adhesion but failed to express molecules promoting leukocyte adhesion, such as E-selectin and vascular cell adhesion molecule 1, even after challenge with TNF-alpha. Collectively, our data suggest that stimulation of endothelial cells by PRBC may have two effects: prevention of parasite clearance through increased cytoadherence and attenuation of leukocyte binding to endothelial cells, thereby preventing deleterious immune reactivity.
authors.affiliation: Hygiene Institut, Abteilung Parasitologie, Universität Heidelberg, Heidelberg, Germany.
authors.forename: Nicola K
authors.initials: NK
authors.lastname: Viebig
authors.forename: Ulrich
authors.initials: U
authors.lastname: Wulbrand
authors.forename: Reinhold
authors.initials: R
authors.lastname: Förster
authors.forename: Katherine T
authors.initials: KT
authors.lastname: Andrews
authors.forename: Michael
authors.initials: M
authors.lastname: Lanzer
authors.forename: Percy A
authors.initials: PA
authors.lastname: Knolle
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002450:Cell Communication; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology*; D004912:Erythrocytes / Q000469:parasitology* / Q000502:physiology; D020869:Gene Expression Profiling; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D010963:Plasmodium falciparum / Q000472:pathogenicity*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1