The relative contribution of IL-4 receptor signaling and IL-10 to susceptibility to Leishmania major.
The roles of IL-10 and IL-4 receptor signaling were evaluated in a murine model of Leishmania major infection. In previous studies the L. major substrain LV39 caused progressive, nonhealing lesions in BALB/c mice deficient for IL-4R alpha-chain (IL-4R alpha), while substrain IR173 was highly controlled. To explore whether IL-10 is responsible for inducing susceptibility to LV39, wild-type and IL-4R alpha(-/-) mice were treated with anti-IL-10R mAb, and in a genetic approach, the IL-4R alpha(-/-) mice were crossed with BALB/c IL-10(-/-) mice. In contrast to the lack of resistance conferred by IL-4R alpha gene deletion, partial resistance to LV39 was conferred by IL-10 gene deletion or treatment of BALB/c mice with anti-IL-10R mAb. Lesion sizes and LV39 parasite numbers were further and dramatically reduced in both anti-IL-10R-treated IL-4R alpha(-/-) mice and IL-4R alpha x IL-10 double knockouts. Anti-IL-10R mAb treatment further suppressed parasite growth in IL-4R alpha(-/-) mice infected with L. major IR173. Production of IFN-gamma was only increased relative to wild-type or littermate controls in IL-4R alpha(-/-) mice with complementary defects in IL-10. Comparisons of IFN-gamma-treated infected macrophages in vitro indicated that LV39 required 25- to 500-fold greater concentrations of IFN-gamma than IR173-infected macrophages to achieve a similar efficiency of parasite killing. These studies suggest that regardless of parasite substrain, IL-10 is as important as IL-4/IL-13 in promoting susceptibility to L. major and even more so for those substrains that are relatively resistant to IFN-gamma mediated killing.
Department of Immunology, George Washington University Medical Center, Washington, DC 20037, USA. nnoben@gwu.edu
Nancy
N
Noben-Trauth
Rosalia
R
Lira
Hisashi
H
Nagase
William E
WE
Paul
David L
DL
Sacks
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D015704:CD4 Antigens / Q000276:immunology; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate / Q000235:genetics; D007274:Injections, Intraperitoneal; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018320:Leishmania major / Q000254:growth & development / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000276:immunology* / Q000469:parasitology / Q000517:prevention & control; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018123:Receptors, Interleukin / Q000276:immunology; D053701:Receptors, Interleukin-10; D019948:Receptors, Interleukin-4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013045:Species Specificity
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; D019948:Receptors, Interleukin-4; D016753:Interleukin-10