Tumor necrosis factor α in the pathogenesis of cerebral malaria

Abstract

Physiologically in the brain, cytokines such as tumor necrosis factor-alpha (TNα) are released by the immune system and can modulate neurological responses. Conversely, the central nervous system (CNS) is also able to modulate cytokine production. In the case of CNS disorders, cytokine release may be modified. Cerebral malaria (CM) is a complication of Plasmodium falciparum infection in humans and is characterized by a reversible encephalopathy with seizures and loss of consciousness. Central clinical signs are partly due to sequestration of parasitized red blood cells in the brain microvasculature due to interactions between parasite proteins and adhesion molecules. TNFα is produced and released by host cells following exposure to various malarial antigens. The increase of TNFα release is responsible for the overexpression of adhesion molecules. This article reviews the involvement of TNFα in cerebral malaria and the relation with all the processes involved in this pathology. It shows that (i) TNFα levels are increased in plasma and brain but with no clear correlation between TNFα levels and occurrence and severity of CM; (ii) TNFα is responsible for intercellular adhesion molecule-1 upregulation in CM, the relation being less clear for other adhesion molecules; (iii) TNFα receptors are upregulated in CM, with TNF receptor 2 (TNFR2) showing a higher upregulation than TNFR1 in vivo; (iv) in murine CM, low doses of TNFα seem to protect from CM, whereas excess TNFα induces CM and anti-TNFα therapies (antibodies, pentoxifylline) did not show any efficiency in protection from CM. Moreover, the involvement of lymphotoxin a, which shares with TNFα the same receptors with similar affinity, appears to be an interesting target for further investigation.

DOI: 10.1007/s00018-003-2347-x

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@article{Gimenez2003TumorNF, title={Tumor necrosis factor α in the pathogenesis of cerebral malaria}, author={F. Gimenez and S. Barraud de Lagerie and C. Fernandez and P. Pino and D. Mazier}, journal={Cellular and Molecular Life Sciences CMLS}, year={2003}, volume={60}, pages={1623-1635} }