A pathogenic role of IL-12 in blood-stage murine malaria lethal strain Plasmodium berghei NK65 infection.
We studied whether the infection with a blood-stage murine malaria lethal Plasmodium berghei NK65 induces IL-12 production, and if so, how the IL-12 production is involved in the protection or pathogenesis. The infection of C57BL/6 mice enhanced mRNA expression of IL-12 p40 and also IFN-gamma, IL-4, and IL-10 in both spleen and liver during the early course of the infection. It also enhanced the mRNA expression of TNF-alpha, Fas ligand, and cytokine-inducible nitric oxide synthase. Increased IL-12 p40 production was also observed in the culture supernatant of spleen cells and in sera of infected mice. In addition, the infection caused massive liver injury with elevated serum glutamic-oxaloacetic transaminase and serum glutamic-pyruvic transaminase activities and body weight loss. Treatment of these infected mice with neutralizing mAb against IL-12 prolonged the survival and diminished the liver injury with reduced elevation of serum serum glutamic-oxaloacetic transaminase and serum glutamic-pyruvic transaminase activities and decreased body weight loss. However, the anti-IL-12 treatment did not affect parasitemia, and all these mice eventually died. Similar results were obtained when infected mice were treated with neutralizing mAb against IFN-gamma. Moreover, anti-IL-12 treatment greatly reduced the secretion and mRNA expression of IFN-gamma in both spleen and liver. These results suggest that the lethal P. berghei NK65 infection induces IL-12 production and that the IL-12 is involved in the pathogenesis of liver injury via IFN-gamma production rather than the protection.
Yoshimoto
T
T
Department of Allergology, Institute of Medical Science, The University of Tokyo, Japan.
Takahama
Y
Y
Wang
C R
CR
Yoneto
T
T
Waki
S
S
Nariuchi
H
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D005260:Female; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008288:Malaria / Q000209:etiology* / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei / Q000254:growth & development* / Q000276:immunology / Q000472:pathogenicity; D013154:Spleen / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D018664:Interleukin-12; D007371:Interferon-gamma