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Uric acid is a mediator of the Plasmodium falciparum-induced inflammatory response.

Orengo JM, Leliwa-Sytek A, Evans JE, Evans B, van de Hoef D, Nyako M, Day K, Rodriguez A - PLoS ONE (2009)

Bottom Line: The identification of pro-inflammatory molecules derived from Plasmodium is essential to understand the mechanisms of pathogenesis and to develop targeted interventions.We found that human erythrocytes infected with Plasmodium falciparum gradually accumulate hypoxanthine in their late stages of development.Both treatments significantly reduce the secretion of TNF, IL-6, IL-1beta and IL-10 from human cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Parasitology, NYU School of Medicine, New York, NY, USA.

ABSTRACT

Background: Malaria triggers a high inflammatory response in the host that mediates most of the associated pathologies and contributes to death. The identification of pro-inflammatory molecules derived from Plasmodium is essential to understand the mechanisms of pathogenesis and to develop targeted interventions. Uric acid derived from hypoxanthine accumulated in infected erythrocytes has been recently proposed as a mediator of inflammation in rodent malaria.

Methods and findings: We found that human erythrocytes infected with Plasmodium falciparum gradually accumulate hypoxanthine in their late stages of development. To analyze the role of hypoxanthine-derived uric acid induced by P. falciparum on the inflammatory cytokine response from human blood mononuclear cells, cultures were treated with allopurinol, to inhibit uric acid formation from hypoxanthine, or with uricase, to degrade uric acid. Both treatments significantly reduce the secretion of TNF, IL-6, IL-1beta and IL-10 from human cells.

Conclusions and significance: Uric acid is a major contributor of the inflammatory response triggered by P. falciparum in human peripheral blood mononuclear cells. Since the inflammatory reaction induced by P. falciparum is considered a major cause of malaria pathogenesis, identifying the mechanisms used by the parasite to induce the host inflammatory response is essential to develop urgently needed therapies against this disease.

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Related in: MedlinePlus

Time course of P. falciparum-induced TNF, IL-6 and IL-1β release from PBMCs in the presence of allopurinol.PBMCs were incubated with mature P. falciparum infected erythrocytes (squares), uninfected erythrocytes (circles) or media alone (diamonds) at a ratio of (5∶1; erythrocyte∶PBMC) for the indicated time points in the presence (white symbols) or absence (black symbols) of 2 mM allopurinol. Incubation media were collected and TNF (A), IL-6 (B), IL-1β (C) or IL-10 (D) concentrations were determined by ELISA. Data represent the average of triplicated samples with standard deviations. *, indicates significant differences (p<0.05) in cytokine release by PBMCs incubated with iRBCs when compared to IRBCs in the presence of allopurinol.
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pone-0005194-g004: Time course of P. falciparum-induced TNF, IL-6 and IL-1β release from PBMCs in the presence of allopurinol.PBMCs were incubated with mature P. falciparum infected erythrocytes (squares), uninfected erythrocytes (circles) or media alone (diamonds) at a ratio of (5∶1; erythrocyte∶PBMC) for the indicated time points in the presence (white symbols) or absence (black symbols) of 2 mM allopurinol. Incubation media were collected and TNF (A), IL-6 (B), IL-1β (C) or IL-10 (D) concentrations were determined by ELISA. Data represent the average of triplicated samples with standard deviations. *, indicates significant differences (p<0.05) in cytokine release by PBMCs incubated with iRBCs when compared to IRBCs in the presence of allopurinol.

Mentions: We next characterized the inflammatory cytokine response at different times after incubation of PBMCs with P. falciparum-infected erythrocytes. We found that TNF secretion was inhibited at early time points, but was not greatly affected at 24 h (Fig. 4A). These results suggest that the early TNF response is mediated by hypoxanthine degradation into uric acid, but that additional inflammatory parasite-derived molecules trigger the late secretion of TNF. Similar results were found for IL-6, IL-1β and IL-10, although the allopurinol-induced inhibition persisted at 24 h in the case of IL-1β (Fig. 4 B–D).


Uric acid is a mediator of the Plasmodium falciparum-induced inflammatory response.

Orengo JM, Leliwa-Sytek A, Evans JE, Evans B, van de Hoef D, Nyako M, Day K, Rodriguez A - PLoS ONE (2009)

Time course of P. falciparum-induced TNF, IL-6 and IL-1β release from PBMCs in the presence of allopurinol.PBMCs were incubated with mature P. falciparum infected erythrocytes (squares), uninfected erythrocytes (circles) or media alone (diamonds) at a ratio of (5∶1; erythrocyte∶PBMC) for the indicated time points in the presence (white symbols) or absence (black symbols) of 2 mM allopurinol. Incubation media were collected and TNF (A), IL-6 (B), IL-1β (C) or IL-10 (D) concentrations were determined by ELISA. Data represent the average of triplicated samples with standard deviations. *, indicates significant differences (p<0.05) in cytokine release by PBMCs incubated with iRBCs when compared to IRBCs in the presence of allopurinol.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2667251&req=5

pone-0005194-g004: Time course of P. falciparum-induced TNF, IL-6 and IL-1β release from PBMCs in the presence of allopurinol.PBMCs were incubated with mature P. falciparum infected erythrocytes (squares), uninfected erythrocytes (circles) or media alone (diamonds) at a ratio of (5∶1; erythrocyte∶PBMC) for the indicated time points in the presence (white symbols) or absence (black symbols) of 2 mM allopurinol. Incubation media were collected and TNF (A), IL-6 (B), IL-1β (C) or IL-10 (D) concentrations were determined by ELISA. Data represent the average of triplicated samples with standard deviations. *, indicates significant differences (p<0.05) in cytokine release by PBMCs incubated with iRBCs when compared to IRBCs in the presence of allopurinol.
Mentions: We next characterized the inflammatory cytokine response at different times after incubation of PBMCs with P. falciparum-infected erythrocytes. We found that TNF secretion was inhibited at early time points, but was not greatly affected at 24 h (Fig. 4A). These results suggest that the early TNF response is mediated by hypoxanthine degradation into uric acid, but that additional inflammatory parasite-derived molecules trigger the late secretion of TNF. Similar results were found for IL-6, IL-1β and IL-10, although the allopurinol-induced inhibition persisted at 24 h in the case of IL-1β (Fig. 4 B–D).

Bottom Line: The identification of pro-inflammatory molecules derived from Plasmodium is essential to understand the mechanisms of pathogenesis and to develop targeted interventions.We found that human erythrocytes infected with Plasmodium falciparum gradually accumulate hypoxanthine in their late stages of development.Both treatments significantly reduce the secretion of TNF, IL-6, IL-1beta and IL-10 from human cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Parasitology, NYU School of Medicine, New York, NY, USA.

ABSTRACT

Background: Malaria triggers a high inflammatory response in the host that mediates most of the associated pathologies and contributes to death. The identification of pro-inflammatory molecules derived from Plasmodium is essential to understand the mechanisms of pathogenesis and to develop targeted interventions. Uric acid derived from hypoxanthine accumulated in infected erythrocytes has been recently proposed as a mediator of inflammation in rodent malaria.

Methods and findings: We found that human erythrocytes infected with Plasmodium falciparum gradually accumulate hypoxanthine in their late stages of development. To analyze the role of hypoxanthine-derived uric acid induced by P. falciparum on the inflammatory cytokine response from human blood mononuclear cells, cultures were treated with allopurinol, to inhibit uric acid formation from hypoxanthine, or with uricase, to degrade uric acid. Both treatments significantly reduce the secretion of TNF, IL-6, IL-1beta and IL-10 from human cells.

Conclusions and significance: Uric acid is a major contributor of the inflammatory response triggered by P. falciparum in human peripheral blood mononuclear cells. Since the inflammatory reaction induced by P. falciparum is considered a major cause of malaria pathogenesis, identifying the mechanisms used by the parasite to induce the host inflammatory response is essential to develop urgently needed therapies against this disease.

Show MeSH
Related in: MedlinePlus