Locally up-regulated lymphotoxin alpha, not systemic tumor necrosis factor alpha, is the principle mediator of murine cerebral malaria


Engwerda, CR; Mynott, TL; Sawhney, S; de Souza, JB; Bickle, QD; Kaye, PM; (2002) Locally up-regulated lymphotoxin alpha, not systemic tumor necrosis factor alpha, is the principle mediator of murine cerebral malaria. The Journal of experimental medicine, 195 (10). pp. 1371-7. ISSN 0022-1007 DOI: https://doi.org/10.1084/jem.20020128

[img]
Preview
Text - Published Version
License:

Download (176kB) | Preview

Abstract

Cerebral malaria (CM) causes death in children and nonimmune adults. TNF-alpha has been thought to play a key role in the development of CM. In contrast, the role of the related cyto-kine lymphotoxin alpha (LTalpha) in CM has been overlooked. Here we show that LTalpha, not TNFalpha, is the principal mediator of murine CM. Mice deficient in TNFalpha (B6.TNFalpha-/-) were as susceptible to CM caused by Plasmodium berghei (ANKA) as C57BL/6 mice, and died 6 to 8 d after infection after developing neurological signs of CM, associated with perivascular brain hemorrhage. Significantly, the development of CM in B6.TNFalpha-/- mice was not associated with increased intracellular adhesion molecule (ICAM)-1 expression on cerebral vasculature and the intraluminal accumulation of complement receptor 3 (CR3)-positive leukocytes was moderate. In contrast, mice deficient in LTalpha (B6.LTalpha-/-) were completely resistant to CM and died 11 to 14 d after infection with severe anemia and hyperparasitemia. No difference in blood parasite burden was found between C57BL/6, B6.TNFalpha-/-, and B6.LTalpha-/- mice at the onset of CM symptoms in the two susceptible strains. In addition, studies in bone marrow (BM) chimeric mice showed the persistence of cerebral LTalpha mRNA after irradiation and engraftment of LTalpha-deficient BM, indicating that LTalpha originated from a radiation-resistant cell population.

Item Type: Article
Keywords: Animal, Bone Marrow Transplantation, Brain/blood supply/parasitology/pathology, Gene Deletion, Immunohistochemistry, Intercellular Adhesion Molecule-1/metabolism, Leukocytes/metabolism/radiation effects, Lymphotoxin/genetics/*metabolism, Macrophage-1 Antigen/metabolism, Malaria, Cerebral/*blood/*metabolism/parasitology, Mice, Mice, Inbred C57BL, Plasmodium berghei/physiology, RNA, Messenger/genetics/metabolism, Radiation Chimera, Radiation Tolerance, Reverse Transcriptase Polymerase Chain Reaction, Support, Non-U.S. Gov't, Tumor Necrosis Factor/deficiency/genetics/*metabolism, Up-Regulation, Animal, Bone Marrow Transplantation, Brain, blood supply, parasitology, pathology, Gene Deletion, Immunohistochemistry, Intercellular Adhesion Molecule-1, metabolism, Leukocytes, metabolism, radiation effects, Lymphotoxin, genetics, metabolism, Macrophage-1 Antigen, metabolism, Malaria, Cerebral, blood, metabolism, parasitology, Mice, Mice, Inbred C57BL, Plasmodium berghei, physiology, RNA, Messenger, genetics, metabolism, Radiation Chimera, Radiation Tolerance, Reverse Transcriptase Polymerase Chain Reaction, Support, Non-U.S. Gov't, Tumor Necrosis Factor, deficiency, genetics, metabolism, Up-Regulation
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Immunology and Infection
Research Centre: Malaria Centre
PubMed ID: 12021316
Web of Science ID: 176110900013
URI: http://researchonline.lshtm.ac.uk/id/eprint/16320

Statistics


Download activity - last 12 months
Downloads since deposit
263Downloads
308Hits
Accesses by country - last 12 months
Accesses by referrer - last 12 months
Impact and interest
Additional statistics for this record are available via IRStats2

Actions (login required)

Edit Item Edit Item