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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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Related in: MedlinePlus

α-C-GalCer induces a prolonged in vivo maturation of DCs compared to α-GalCer. Groups of 3 WT mice were injected i.p. with 1 μg α-GalCer or α-C-GalCer, or with nothing, and 2, 6, or 24 hours later splenocytes were collected and subjected to FACS analysis. CD11c+ cells were gated and analyzed for their levels of (a) MHC class II, (b) CD86, and (c) CD40 at the different time points after glycolipid administration. Also shown are isotype control stainings obtained from the maximally activated, 24-hour, α-GalCer-treated splenocyte populations, gated on CD11c+ cells. The numbers next to each histogram tracing represent the mean fluorescence intensity for that tracing. The data shown come from one of four experiments with similar results.
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fig4: α-C-GalCer induces a prolonged in vivo maturation of DCs compared to α-GalCer. Groups of 3 WT mice were injected i.p. with 1 μg α-GalCer or α-C-GalCer, or with nothing, and 2, 6, or 24 hours later splenocytes were collected and subjected to FACS analysis. CD11c+ cells were gated and analyzed for their levels of (a) MHC class II, (b) CD86, and (c) CD40 at the different time points after glycolipid administration. Also shown are isotype control stainings obtained from the maximally activated, 24-hour, α-GalCer-treated splenocyte populations, gated on CD11c+ cells. The numbers next to each histogram tracing represent the mean fluorescence intensity for that tracing. The data shown come from one of four experiments with similar results.

Mentions: We found that the first marker to show upregulation on CD11c+ DCs after injection of either glycolipid was MHC class II. α-GalCer-treated mice showed increased expression of this marker as soon as 2 hours after injection, while α-C-GalCer-treated mice showed increased expression 6 hours after injection (Figure 4(a)). By 24 hours posttreatment, we saw the highest MHC class II expression on CD11c+ DCs from mice injected with either α-GalCer or α-C-GalCer, with α-GalCer-treated mice expressing slightly more marker than α-C-GalCer-treated mice (Figure 4(a)).


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 induces a prolonged in vivo maturation of DCs compared to α-GalCer. Groups of 3 WT mice were injected i.p. with 1 μg α-GalCer or α-C-GalCer, or with nothing, and 2, 6, or 24 hours later splenocytes were collected and subjected to FACS analysis. CD11c+ cells were gated and analyzed for their levels of (a) MHC class II, (b) CD86, and (c) CD40 at the different time points after glycolipid administration. Also shown are isotype control stainings obtained from the maximally activated, 24-hour, α-GalCer-treated splenocyte populations, gated on CD11c+ cells. The numbers next to each histogram tracing represent the mean fluorescence intensity for that tracing. The data shown come from one of four experiments with similar results.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4: α-C-GalCer induces a prolonged in vivo maturation of DCs compared to α-GalCer. Groups of 3 WT mice were injected i.p. with 1 μg α-GalCer or α-C-GalCer, or with nothing, and 2, 6, or 24 hours later splenocytes were collected and subjected to FACS analysis. CD11c+ cells were gated and analyzed for their levels of (a) MHC class II, (b) CD86, and (c) CD40 at the different time points after glycolipid administration. Also shown are isotype control stainings obtained from the maximally activated, 24-hour, α-GalCer-treated splenocyte populations, gated on CD11c+ cells. The numbers next to each histogram tracing represent the mean fluorescence intensity for that tracing. The data shown come from one of four experiments with similar results.
Mentions: We found that the first marker to show upregulation on CD11c+ DCs after injection of either glycolipid was MHC class II. α-GalCer-treated mice showed increased expression of this marker as soon as 2 hours after injection, while α-C-GalCer-treated mice showed increased expression 6 hours after injection (Figure 4(a)). By 24 hours posttreatment, we saw the highest MHC class II expression on CD11c+ DCs from mice injected with either α-GalCer or α-C-GalCer, with α-GalCer-treated mice expressing slightly more marker than α-C-GalCer-treated mice (Figure 4(a)).

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