Control of Leishmania major infection in mice lacking TNF receptors.
TNF participates in the induction of nitric oxide (NO) production and macrophage activation, leading to the elimination of intracellular pathogens. We previously found that TNF receptor p55-deficient mice (TNFRp55-/-) control replication of Leishmania major in vivo but fail to resolve their lesions. Here we report that mice lacking the p75 receptor (TNFRp75-/-) or both receptors (TNFRp55p75-/-), also control parasite replication, albeit mice lacking the p55 receptor (either TNFRp55-/- or TNFRp55p75-/-) are delayed in their elimination of L. major compared with controls. All TNF receptor-deficient mice developed a Thl-type immune response and up-regulated inducible NO synthase (iNOS) mRNA gene expression in lesions during infection. Thus, neither TNF receptor appears to be absolutely required for NO production or elimination of L. major in vivo. In vitro, however, while macrophages from naive TNFRp75-/- mice could be activated to produce NO and kill L. major, we observed a defect in NO production and parasite killing by resident peritoneal macrophages from naive TNFRp55-/- or TNFRp55p75-/- mice. However, when macrophages were elicited with leishmanial Ag from 4-wk-infected TNFRp55-/- or TNFRp55p75-/- mice, they produced NO and were leishmanicidal. These data suggest that the TNFRp75 plays no essential role in L. major infection in mice and that the p55 receptor may be required for optimal macrophage activation. However, the results also show that a mechanism exists by which macrophages can be primed in vivo during L. major infection to produce NO and kill L. major in the absence of signaling through either of the TNF receptors.
Nashleanas
M
M
University of Pennsylvania School of Veterinary Medicine, Philadelphia 19104, USA.
Kanaly
S
S
Scott
P
P
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D018320:Leishmania major / Q000254:growth & development / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D008262:Macrophage Activation / Q000235:genetics; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000096:biosynthesis; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D015703:Antigens, CD; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse