Tumor necrosis factor (TNF) receptor-1 (TNFp55) signal transduction and macrophage-derived soluble TNF are crucial for nitric oxide-mediated Trypanosoma congolense parasite killing.

TitleTumor necrosis factor (TNF) receptor-1 (TNFp55) signal transduction and macrophage-derived soluble TNF are crucial for nitric oxide-mediated Trypanosoma congolense parasite killing.
Publication TypeJournal Article
Year of Publication2007
AuthorsMagez, S., M. Radwanska, M. Drennan, L. Fick, T. Nath Baral, N. Allie, M. Jacobs, S. Nedospasov, F. Brombacher, B. Ryffel, and P. De Baetselier
JournalJ Infect Dis
Volume196
Issue6
Pagination954-62
Date Published2007 Sep 15
ISSN0022-1899
KeywordsAnimals, Cells, Cultured, Liver, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, Neutrophils, Nitric Oxide, Parasitemia, Receptors, Tumor Necrosis Factor, Type I, Signal Transduction, Trypanosoma congolense, Trypanosomiasis, African, Tumor Necrosis Factor-alpha
Abstract

Control of Trypanosoma congolense infections requires an early cell-mediated immune response. To unravel the role of tumor necrosis factor (TNF) in this process, 6 different T. congolense strains were used in 6 different gene-deficient mouse models that included TNF(-/-), TNF receptor-1 (TNFp55)(-/-), and TNF receptor-2 (TNFp75)(-/-) mice, 2 cell type-specific TNF(-/-) mice, as well as TNF-knock-in mice that expressed only membrane-bound TNF. Our results indicate that soluble TNF produced by macrophages/neutrophils and TNFp55 signaling are essential and sufficient to control parasitemia. The downstream mechanism in the control of T. congolense infection depends on inducible nitric oxide synthase activation in the liver. Such a role for nitric oxide is corroborated ex vivo, because the inhibitor N(G)-monomethyl-l-arginine blocks the trypanolytic activity of the adherent liver cell population, whereas exogenous interferon- gamma that stimulates nitric oxide production enhances parasite killing. In conclusion, the control of T. congolense infection depends on macrophage/neutrophil-derived soluble TNF and intact TNFp55 signaling, which induces trypanolytic nitric oxide.

DOI10.1086/520815
Alternate JournalJ. Infect. Dis.
PubMed ID17703428