In vivo IL-12 production and IL-12 receptors beta1 and beta2 mRNA expression in the spleen are differentially up-regulated in resistant B6 and susceptible A/J mice during early blood-stage Plasmodium chabaudi AS malaria.
As previously reported, blood-stage Plasmodium chabaudi AS malaria is lethal by days 10-12 postinfection in susceptible A/J mice that mount an early, predominantly Th2 response. In contrast, resistant C57BL/6 (B6) mice clear the infection by 4 wk with an early Th1 response. In this study, we analyzed in vivo production of IL-12, a potent Th1-inducing cytokine, during the first 5 days after P. chabaudi AS infection in these mice. By day 2, serum IL-12 p70 levels were significantly increased in B6 mice over basal levels and were also significantly higher compared with A/J mice that showed no significant changes in serum p70 levels after infection. Splenectomy of resistant B6 mice before infection demonstrated that the spleen is the major source of systemic IL-12 in these hosts. Splenic mRNA levels of both p40 and p35 were significantly higher in A/J mice; however, the ratios of p40/p35 mRNA levels were similarly up-regulated in both strains. Furthermore, B6 but not A/J mice showed significant up-regulation of splenic IL-12R beta2 mRNA over basal levels by days 3 and 4, coincident with sustained up-regulation of splenic IFN-gamma mRNA levels on days 3-5. However, IL-12R beta1 mRNA levels in the spleen were similarly up-regulated in both mouse strains by day 3. Taken together, these data suggest that high systemic IL-12 production, accompanied by an early and sustained up-regulation of both IL-12R beta1 and beta2 mRNA levels in the spleen, as occurs in resistant B6 mice, appears to preferentially induce protective Th1 responses against blood-stage malaria.
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McGill University Centre for the Study of Host Resistance, and Montreal General Hospital Research Institute, Montreal, Quebec, Canada.
Stevenson
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D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000097:blood; D007700:Kinetics; D008288:Malaria / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D016788:Plasmodium chabaudi; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000235:genetics*; D053707:Receptors, Interleukin-12; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity; D013154:Spleen / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D015854:Up-Regulation