Production of IL-12 by macrophages infected with Toxoplasma gondii depends on the parasite genotype.
Three clonal strain types (I, II, and III) of Toxoplasma gondii predominate worldwide. The outcome of infection in mice is highly dependent on the parasite genotype with type I strains being uniformly virulent, while types II and III are nonvirulent. Interactions with the innate immune response play a major role in determining the outcome of infection in the murine model. To identify key early differences in the innate immune response that contribute to pathogenesis, we examined the cytokine production of macrophages after in vitro infection with parasites of virulent type I and nonvirulent type II genotypes. Infection with type II strain parasites stimulated the production of proinflammatory cytokines, and particularly high levels of the Th1-polarizing cytokine, IL-12. Infection with type II strain parasites stimulated NF-kappaB nuclear translocation at early time points and led to the up-regulation of mRNA levels of IL-12 and other proinflammatory cytokines that was dependent on the myeloid differentiation factor 88 signaling pathway. Induction of IL-12 required active invasion by live parasites and was not blocked by infection with virulent type I strain parasites, arguing against an active inhibition of signaling. Our findings suggest that early induction of high levels of IL-12 by macrophages infected with type II strain parasites may contribute to more effective control.
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Paul M
PM
Robben
Dana G
DG
Mordue
Steven M
SM
Truscott
Kiyoshi
K
Takeda
Shizuo
S
Akira
L David
LD
Sibley
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D005838:Genotype; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D007700:Kinetics; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000378:metabolism; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D013045:Species Specificity; D014122:Toxoplasma / Q000235:genetics* / Q000276:immunology* / Q000472:pathogenicity; D014774:Virulence / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D011971:Receptors, Immunologic; D018664:Interleukin-12