title: IL-4-independent inhibition of IL-12 responsiveness during Leishmania amazonensis infection.
abstract: Leishmania amazonensis induces a nonhealing infection in C3H mice, whereas infection with Leishmania major is self-healing. We found that C3H mice infected with L. amazonensis exhibited decreased IL-12 production, which could account for the susceptibility to this organism. However, exogenous IL-12 administration failed to induce a healing immune response. The failure of L. amazonensis-infected C3H mice to respond to IL-12 was associated with a specific defect in IL-12 receptor beta2 (IL-12Rbeta2) mRNA expression by CD4+ T cells. Furthermore, decreased IL-12Rbeta2 mRNA expression correlated with a decrease in the IL-12-signaling capacity of the lymph node (LN) cells. IL-4 did not contribute to susceptibility or down-regulation of the IL-12Rbeta2 subunit, because IL-4-/- mice remained susceptible to L. amazonensis infection, even after IL-12 administration, and CD4+ cells from infected IL-4-/- mice also had reduced expression of IL-12Rbeta2 mRNA. These results demonstrate that regulation of the IL-12 receptor, independent of IL-4, is a point of control for the immune response to leishmaniasis. In contrast to experimental L. major infections, where host genetics control susceptibility, these studies demonstrate that the lack of IL-12 responsiveness may be dictated by the pathogen, rather than the host.
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia 19104, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Jones
authors.forename: L U
authors.initials: LU
authors.lastname: Buxbaum
authors.forename: P
authors.initials: P
authors.lastname: Scott
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000502:physiology; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018320:Leishmania major / Q000276:immunology; D007894:Leishmania mexicana / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D053707:Receptors, Interleukin-12; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D000953:Antigens, Protozoan; C508443:Il12rb2 protein, mouse; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma