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Thromb Haemost 2005; 94(02): 341-346
DOI: 10.1160/TH05-01-0053
Theme Issue Article
Schattauer GmbH

Role of human brain microvascular endothelial cells during central nervous system infection

Significance of indoleamine 2,3-dioxygenase in antimicrobial defence and immunoregulation
Rüdiger Adam
1   Pädiatrische Infektiologie, Klinik für Allgemeine Pädiatrie, Universitätsklinikum, Düsseldorf, Germany
,
Daniel Rüssing
2   Institut für Medizinische Mikrobiologie, Heinrich-Heine-Universität, Düsseldorf, Germany
,
Ortwin Adams
3   Institut für Virologie, Heinrich-Heine-Universität, Düsseldorf, Germany
,
Aziz Ailyati
2   Institut für Medizinische Mikrobiologie, Heinrich-Heine-Universität, Düsseldorf, Germany
,
Kwang Sik Kim
4   Pediatric Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, USA
,
Horst Schroten
1   Pädiatrische Infektiologie, Klinik für Allgemeine Pädiatrie, Universitätsklinikum, Düsseldorf, Germany
,
Walter Däubener
2   Institut für Medizinische Mikrobiologie, Heinrich-Heine-Universität, Düsseldorf, Germany
› Author AffiliationsFinancial support: This work was supportby ed the Deutsche Forschungsgemeinschaft, Schwerpunktprogramm “Endothel and Infection”, Project DA 221/3–1.
Further Information

Publication History

Received: 21 January 2005

Accepted after major revision: 23 May 2005

Publication Date:
05 December 2017 (online)

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Summary

The cerebral endothelium is involved both in regulatinthinflux g e of immune cells into the brain and in modifying immunological reactions within the CNS. A number of human pathogens may cause encephalitis or meningitis when this important protective barrier is impaired. We have previously shown that interferon- γ activated human brain microvascular endothelial cells (HBMEC) restrict the growth of bacteria and parasites. We now provide evidence that HBMEC are also capable of inhibiting viral replication after stimulation with IFN-γ, an effect further augmented by costimulation with IL-1. This antiviral effect was completely blocked in the presence of L-tryptophan, indicating the induction of the tryptophan degrading enzyme indoleamine 2,3-dioxygenase (IDO) to be responsible for the observed antiviral effect. Apart from exerting antimicrobial effects tryptophan depletetion has also been described as a regulatory mechanism in T cell responses to both allo- and autoantigens. We were able to demonstrate that IDO mediated degradation of L-tryptohan in HBMEC is responsible for a significant reduction inT lymphocyte proliferation. Resupplementation of L-tryptophan and restoration of initial T cell responses demonstrated the central role of this essential amino acid in the reduction of T-cell proliferation. Brain endothelial cells appear to limit microbial expansion in the CNS by local degradation of tryptophan, thus acting in concert with other IDO-positive cell populations on the parenchymal side of the blood-brain barrier such as astrocytes, microglia and neurons. Since all dietary tryptophan must cross the blood-brain barrier, the microvascular endothelial cells may play a key role in restricting tryptophan influx from the bloodstream into the brain. As deleterious effects of brain infections can often be attributed to subsequently invading immune cells, an IDO-mediated reduction of lymphocyte proliferation may be beneficial for preventing collateral brain damage.

Keywords

Meningitis - encephalitis - IDO - kynurenine - herpes simplex virus
 

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