title: Mice lacking the TNF receptor p55 fail to resolve lesions caused by infection with Leishmania major, but control parasite replication.
abstract: TNF is involved in host resistance to several pathogens. Recently it was found that mice lacking the p55 receptor for TNF (TNFRp55 -/-) do not control growth of the intracellular bacteria, Listeria monocytogenes and Mycobacterium tuberculosis. Here we report that the course of infection in TNFRp55 -/- mice with another intracellular pathogen, the protozoan parasite Leishmania major, is also quite different from normal mice. TNFRp55 -/- mice developed larger lesions than control mice and failed to resolve these lesions. However, they were able to eliminate parasites within the lesions. Histologic analysis indicated that at late stages lesions from TNFRp55 -/- mice appeared similar to lesions associated with cutaneous graft-vs-host disease. Both TNFRp55 -/- and control mice developed a normal Th1-type response during infection. We also found that IFN-gamma-activated macrophages from TNFRp55 -/- mice produced nitric oxide and killed L. major in vitro, which correlated with the ability of TNFRp55 -/- mice to eliminate the parasites in vivo. The production of nitric oxide by macrophages from TNFRp55 -/- mice required the presence of the parasites, however, since in their absence TNF could only synergize with IFN-gamma for nitric oxide production when added to normal, but not TNFRp55 -/-, macrophages. These results indicate that neither macrophage microbicidal activity nor nitric oxide production is absolutely dependent on the p55 receptor for TNF. Furthermore, they uncover a previously undefined role for TNFRp55 in resolution of parasite-induced inflammatory lesions.
authors: Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia 19104, USA.
authors: L Q
authors: LQ
authors: Vieira
authors: M
authors: M
authors: Goldschmidt
authors: M
authors: M
authors: Nashleanas
authors: K
authors: K
authors: Pfeffer
authors: T
authors: T
authors: Mak
authors: P
authors: P
authors: Scott
mesh_terms: D000818:Animals; D001483:Base Sequence; D018320:Leishmania major / Q000254:growth & development* / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000276:immunology* / Q000469:parasitology* / Q000473:pathology; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000096:biosynthesis; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency* / Q000235:genetics*; D018417:Th1 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide