title: Plasmodium falciparum-infected erythrocytes increase intercellular adhesion molecule 1 expression on brain endothelium through NF-kappaB.
abstract: Sequestration of Plasmodium falciparum-infected erythrocytes (Pf-IRBC) in postcapillary brain endothelium is a hallmark of cerebral malaria (CM) pathogenesis. There is a correlation between adherent Pf-IRBC and increased expression of intercellular cell adhesion molecule 1 (ICAM-1), which is also a receptor for Pf-IRBC on human brain microvascular endothelial cells (HBMEC). The underlying mechanism for the increased ICAM-1 expression has not been clearly defined. Therefore, we investigated the mechanisms of ICAM-1 expression on isolated HBMEC after exposure to Pf-IRBC. Ultrastructural characterization of the model confirmed that there was attachment through both Pf-IRBC knobs and HBMEC microvillus protrusions. Pf-IRBC induced a dose- and time-dependent increase in ICAM-1 expression on HBMEC that was specific for human brain endothelium and was not observed with human umbilical vein endothelium. Involvement of both membrane-associated Pf-IRBC proteins and parasite-derived soluble factors with the increase in ICAM-1 expression was demonstrated by surface trypsinization and fractionation. Pf-IRBC exposure induced nuclear translocation of NF-kappaB in HBMEC, which was linked to ICAM-1 expression, as shown by use of specific inhibitors of the transcription factor NF-kappaB and immunocytochemistry. In addition, inhibition of reactive oxygen species decreased Pf-IRBC-induced ICAM-1 expression on HBMEC. Parasite-induced ICAM-1 expression explains the localization of this molecule on brain endothelium in postmortem CM brain samples. By increasing ICAM-1 expression, Pf-IRBC may increase their sequestration, thereby perpetuating CM.
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, 720 Rutland Avenue, Ross 1170, Baltimore, MD 21205, USA.
authors.forename: Abhai K
authors.initials: AK
authors.lastname: Tripathi
authors.forename: David J
authors.initials: DJ
authors.lastname: Sullivan
authors.forename: Monique F
authors.initials: MF
authors.lastname: Stins
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D037621:Artemisinins / Q000494:pharmacology; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D004912:Erythrocytes / Q000469:parasitology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis*; D016328:NF-kappa B / Q000502:physiology*; D010963:Plasmodium falciparum / Q000472:pathogenicity*; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes / Q000494:pharmacology
chemical_list: D037621:Artemisinins; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; D018799:Intercellular Adhesion Molecule-1; C031327:artemisinin