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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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P. falciparum-derived uric acid induces TNF, IL-6 and IL-1β release from PBMCs.PBMCs were incubated with media alone (control), uninfected erythrocytes (RBCs) or P. falciparum-infected erythrocytes (iRBCs) at a ratio of (5∶1; erythrocyte∶PBMC) for 6 h (24 h for IL-10) in the absence (black bars) or presence (white bars) of 2 mM allopurinol (A–D) or 0.1 mg/ml uricase (E–H). Incubation media were collected and TNF (A,E), IL-6 (B,F), IL-1β (C,G) and IL-10 (D,H) concentrations were determined by flow cytometry using cytometric bead array. 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 or uricase.
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pone-0005194-g003: P. falciparum-derived uric acid induces TNF, IL-6 and IL-1β release from PBMCs.PBMCs were incubated with media alone (control), uninfected erythrocytes (RBCs) or P. falciparum-infected erythrocytes (iRBCs) at a ratio of (5∶1; erythrocyte∶PBMC) for 6 h (24 h for IL-10) in the absence (black bars) or presence (white bars) of 2 mM allopurinol (A–D) or 0.1 mg/ml uricase (E–H). Incubation media were collected and TNF (A,E), IL-6 (B,F), IL-1β (C,G) and IL-10 (D,H) concentrations were determined by flow cytometry using cytometric bead array. 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 or uricase.

Mentions: To determine if hypoxanthine degradation plays a role in P. falciparum induced production of inflammatory mediators, we used allopurinol, an inhibitor of xanthine oxidoreductase that prevents the formation of uric acid from hypoxanthine or xanthine [11]. Despite having toxic effects on other parasites, allopurinol did not inhibit the growth of P. falciparum in vitro (Fig. 2D) or in vivo [8], [12]. We incubated PBMCs with P. falciparum-infected erythrocytes in late developmental stage (schizonts) in the presence or absence of allopurinol to inhibit hypoxanthine degradation. We found that the release of TNF, IL-6, IL-1β and IL-10 by PBMCs was significantly inhibited by allopurinol (Fig. 3A–D), suggesting that hypoxanthine degradation plays an important role in the inflammatory response induced by P. falciparum.


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)

P. falciparum-derived uric acid induces TNF, IL-6 and IL-1β release from PBMCs.PBMCs were incubated with media alone (control), uninfected erythrocytes (RBCs) or P. falciparum-infected erythrocytes (iRBCs) at a ratio of (5∶1; erythrocyte∶PBMC) for 6 h (24 h for IL-10) in the absence (black bars) or presence (white bars) of 2 mM allopurinol (A–D) or 0.1 mg/ml uricase (E–H). Incubation media were collected and TNF (A,E), IL-6 (B,F), IL-1β (C,G) and IL-10 (D,H) concentrations were determined by flow cytometry using cytometric bead array. 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 or uricase.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0005194-g003: P. falciparum-derived uric acid induces TNF, IL-6 and IL-1β release from PBMCs.PBMCs were incubated with media alone (control), uninfected erythrocytes (RBCs) or P. falciparum-infected erythrocytes (iRBCs) at a ratio of (5∶1; erythrocyte∶PBMC) for 6 h (24 h for IL-10) in the absence (black bars) or presence (white bars) of 2 mM allopurinol (A–D) or 0.1 mg/ml uricase (E–H). Incubation media were collected and TNF (A,E), IL-6 (B,F), IL-1β (C,G) and IL-10 (D,H) concentrations were determined by flow cytometry using cytometric bead array. 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 or uricase.
Mentions: To determine if hypoxanthine degradation plays a role in P. falciparum induced production of inflammatory mediators, we used allopurinol, an inhibitor of xanthine oxidoreductase that prevents the formation of uric acid from hypoxanthine or xanthine [11]. Despite having toxic effects on other parasites, allopurinol did not inhibit the growth of P. falciparum in vitro (Fig. 2D) or in vivo [8], [12]. We incubated PBMCs with P. falciparum-infected erythrocytes in late developmental stage (schizonts) in the presence or absence of allopurinol to inhibit hypoxanthine degradation. We found that the release of TNF, IL-6, IL-1β and IL-10 by PBMCs was significantly inhibited by allopurinol (Fig. 3A–D), suggesting that hypoxanthine degradation plays an important role in the inflammatory response induced by P. falciparum.

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