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A multifactorial mechanism in the superior antimalarial activity of alpha-C-GalCer.

Schmieg J, Yang G, Franck RW, Tsuji M - J. Biomed. Biotechnol. (2009)

Bottom Line: We have previously shown that the C-glycoside analog of alpha-galactosylceramide (alpha-GalCer), alpha-C-GalCer, displays a superior inhibitory activity against the liver stages of the rodent malaria parasite Plasmodium yoelii than its parental glycolipid, alpha-GalCer.In this study, we demonstrate that NK cells, as well as IL-12, are a key contributor for the superior activity displayed by alpha-C-GalCer.Surprisingly, the diminished production of Th2 cytokines, including IL-4, by alpha-C-GalCer has no affect on its superior therapeutic activity relative to alpha-GalCer.

View Article: PubMed Central - PubMed

Affiliation: Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.

ABSTRACT
We have previously shown that the C-glycoside analog of alpha-galactosylceramide (alpha-GalCer), alpha-C-GalCer, displays a superior inhibitory activity against the liver stages of the rodent malaria parasite Plasmodium yoelii than its parental glycolipid, alpha-GalCer. In this study, we demonstrate that NK cells, as well as IL-12, are a key contributor for the superior activity displayed by alpha-C-GalCer. Surprisingly, the diminished production of Th2 cytokines, including IL-4, by alpha-C-GalCer has no affect on its superior therapeutic activity relative to alpha-GalCer. Finally, we show that the in vivo administration of alpha-C-GalCer induces prolonged maturation of dendritic cells (DCs), as well as an enhanced proliferative response of mouse invariant Valpha14 (Valpha14i) NKT cells, both of which may also contribute to some degree to the superior activity of alpha-C-GalCer in vivo.

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α-C-GalCer's superior therapeutic activity against malaria liver stages requires IL-12 and NK cells. (a) Groups of 5 WT or IL-12-deficient BALB/c mice were treated intraperitoneally (i.p.) with 1 μg of either α-C-GalCer or α-GalCer or with nothing 3 days before challenge intravenously with live P. yoelii sporozoites, and then checked for malaria liver stage development. The results are expressed as the average  +/−  SD of 5 mice. (b) Groups of 5 WT C57BL/6 mice were treated i.p. with PBS or anti-asialoGM1 antibody 1 day prior to i.p. injection with 1 μg of α-C-GalCer or α-GalCer, or with nothing. Three days later the mice were challenged with live P. yoelii sporozoites, and then checked for malaria liver stage development. The results are expressed as the average  +/−  SD of 5 mice. The data shown come from one of three experiments with similar results.
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fig2: α-C-GalCer's superior therapeutic activity against malaria liver stages requires IL-12 and NK cells. (a) Groups of 5 WT or IL-12-deficient BALB/c mice were treated intraperitoneally (i.p.) with 1 μg of either α-C-GalCer or α-GalCer or with nothing 3 days before challenge intravenously with live P. yoelii sporozoites, and then checked for malaria liver stage development. The results are expressed as the average +/− SD of 5 mice. (b) Groups of 5 WT C57BL/6 mice were treated i.p. with PBS or anti-asialoGM1 antibody 1 day prior to i.p. injection with 1 μg of α-C-GalCer or α-GalCer, or with nothing. Three days later the mice were challenged with live P. yoelii sporozoites, and then checked for malaria liver stage development. The results are expressed as the average +/− SD of 5 mice. The data shown come from one of three experiments with similar results.

Mentions: In a previous study, we showed that α-C-GalCer's ability to stimulate prolonged IFN-γ production is abrogated in the absence of IL-12 [6]. Since IFN-γ is required for α-C-GalCer's anti-malaria effect, we wanted to see if its superior therapeutic activity against malaria liver stages was abrogated in the absence of IL-12 as well. To address this issue, we first treated both WT and IL-12-deficient mice with equal doses of either glycolipid three days before challenge with sporozoites, and then measured malaria liver stage development. As expected, in WT mice α-C-GalCer suppressed liver stage development to a much greater degree than α-GalCer; however, in IL-12-deficient mice the anti-malaria activity of both glycolipids was totally abolished (Figure 2(a)). Thus, IL-12 is a key factor not only driving α-C-GalCer's superior antimalarial effect, but also mediating the antiplasmodial effect of both glycolipids.


A multifactorial mechanism in the superior antimalarial activity of alpha-C-GalCer.

Schmieg J, Yang G, Franck RW, Tsuji M - J. Biomed. Biotechnol. (2009)

α-C-GalCer's superior therapeutic activity against malaria liver stages requires IL-12 and NK cells. (a) Groups of 5 WT or IL-12-deficient BALB/c mice were treated intraperitoneally (i.p.) with 1 μg of either α-C-GalCer or α-GalCer or with nothing 3 days before challenge intravenously with live P. yoelii sporozoites, and then checked for malaria liver stage development. The results are expressed as the average  +/−  SD of 5 mice. (b) Groups of 5 WT C57BL/6 mice were treated i.p. with PBS or anti-asialoGM1 antibody 1 day prior to i.p. injection with 1 μg of α-C-GalCer or α-GalCer, or with nothing. Three days later the mice were challenged with live P. yoelii sporozoites, and then checked for malaria liver stage development. The results are expressed as the average  +/−  SD of 5 mice. The data shown come from one of three experiments with similar results.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2801455&req=5

fig2: α-C-GalCer's superior therapeutic activity against malaria liver stages requires IL-12 and NK cells. (a) Groups of 5 WT or IL-12-deficient BALB/c mice were treated intraperitoneally (i.p.) with 1 μg of either α-C-GalCer or α-GalCer or with nothing 3 days before challenge intravenously with live P. yoelii sporozoites, and then checked for malaria liver stage development. The results are expressed as the average +/− SD of 5 mice. (b) Groups of 5 WT C57BL/6 mice were treated i.p. with PBS or anti-asialoGM1 antibody 1 day prior to i.p. injection with 1 μg of α-C-GalCer or α-GalCer, or with nothing. Three days later the mice were challenged with live P. yoelii sporozoites, and then checked for malaria liver stage development. The results are expressed as the average +/− SD of 5 mice. The data shown come from one of three experiments with similar results.
Mentions: In a previous study, we showed that α-C-GalCer's ability to stimulate prolonged IFN-γ production is abrogated in the absence of IL-12 [6]. Since IFN-γ is required for α-C-GalCer's anti-malaria effect, we wanted to see if its superior therapeutic activity against malaria liver stages was abrogated in the absence of IL-12 as well. To address this issue, we first treated both WT and IL-12-deficient mice with equal doses of either glycolipid three days before challenge with sporozoites, and then measured malaria liver stage development. As expected, in WT mice α-C-GalCer suppressed liver stage development to a much greater degree than α-GalCer; however, in IL-12-deficient mice the anti-malaria activity of both glycolipids was totally abolished (Figure 2(a)). Thus, IL-12 is a key factor not only driving α-C-GalCer's superior antimalarial effect, but also mediating the antiplasmodial effect of both glycolipids.

Bottom Line: We have previously shown that the C-glycoside analog of alpha-galactosylceramide (alpha-GalCer), alpha-C-GalCer, displays a superior inhibitory activity against the liver stages of the rodent malaria parasite Plasmodium yoelii than its parental glycolipid, alpha-GalCer.In this study, we demonstrate that NK cells, as well as IL-12, are a key contributor for the superior activity displayed by alpha-C-GalCer.Surprisingly, the diminished production of Th2 cytokines, including IL-4, by alpha-C-GalCer has no affect on its superior therapeutic activity relative to alpha-GalCer.

View Article: PubMed Central - PubMed

Affiliation: Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.

ABSTRACT
We have previously shown that the C-glycoside analog of alpha-galactosylceramide (alpha-GalCer), alpha-C-GalCer, displays a superior inhibitory activity against the liver stages of the rodent malaria parasite Plasmodium yoelii than its parental glycolipid, alpha-GalCer. In this study, we demonstrate that NK cells, as well as IL-12, are a key contributor for the superior activity displayed by alpha-C-GalCer. Surprisingly, the diminished production of Th2 cytokines, including IL-4, by alpha-C-GalCer has no affect on its superior therapeutic activity relative to alpha-GalCer. Finally, we show that the in vivo administration of alpha-C-GalCer induces prolonged maturation of dendritic cells (DCs), as well as an enhanced proliferative response of mouse invariant Valpha14 (Valpha14i) NKT cells, both of which may also contribute to some degree to the superior activity of alpha-C-GalCer in vivo.

Show MeSH
Related in: MedlinePlus