Endothelial cells potentiate interferon-γ production in a novel tripartite culture model of human cerebral malaria

PLoS One. 2013 Jul 12;8(7):e69521. doi: 10.1371/journal.pone.0069521. Print 2013.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing / pharmacology
  • B7-1 Antigen / metabolism
  • B7-2 Antigen / metabolism
  • Caspase 1 / metabolism
  • Caspase Inhibitors / pharmacology
  • Cell Culture Techniques
  • Chemokine CXCL10 / metabolism
  • Coculture Techniques
  • Endothelial Cells / drug effects
  • Endothelial Cells / enzymology
  • Endothelial Cells / metabolism*
  • Endothelial Cells / pathology
  • Erythrocytes / drug effects
  • Erythrocytes / enzymology
  • Erythrocytes / parasitology
  • Histocompatibility Antigens Class II / metabolism
  • Humans
  • Immunologic Factors / metabolism
  • Inducible T-Cell Co-Stimulator Ligand / metabolism
  • Inflammation Mediators / metabolism
  • Intercellular Adhesion Molecule-1 / metabolism
  • Interferon-gamma / biosynthesis*
  • Interleukin-10 / biosynthesis
  • Interleukin-1beta / biosynthesis
  • Interleukin-2 / metabolism
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / metabolism
  • Malaria, Cerebral / immunology*
  • Malaria, Cerebral / parasitology
  • Malaria, Cerebral / pathology*
  • Models, Biological*
  • Parasites / drug effects
  • Parasites / physiology
  • Plasmodium falciparum / drug effects
  • Plasmodium falciparum / physiology

Substances

  • Antibodies, Neutralizing
  • B7-1 Antigen
  • B7-2 Antigen
  • CXCL10 protein, human
  • Caspase Inhibitors
  • Chemokine CXCL10
  • Histocompatibility Antigens Class II
  • ICOSLG protein, human
  • Immunologic Factors
  • Inducible T-Cell Co-Stimulator Ligand
  • Inflammation Mediators
  • Interleukin-1beta
  • Interleukin-2
  • Intercellular Adhesion Molecule-1
  • Interleukin-10
  • Interferon-gamma
  • Caspase 1

Grants and funding

This work was supported by a grant from the National Health and Medical Research Council of Australia to NH and a Sir Zelman Cowen Universities Fund grant to JG and NH. LTK was supported by a scholarship from the Ministry of Science, Technology and Innovation, Malaysia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.