Impaired Systemic Production of Prostaglandin E<sub>2</sub>in Children with Cerebral Malaria

Perkins, Douglas J; Hittner, James B.; Mwaikambo, Esther D.; Granger, Donald L.; Weinberg, J. Brice; Anstey, Nicholas M.

doi:10.1086/429332

Cited by 21 publications

(27 citation statements)

References 40 publications

(57 reference statements)

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“…We have observed that these treatments increase CD8 + T cell function during P. yoelii infections, however a correlation of high levels of PGE 2 and COX-2 activation with low incidence of cerebral malaria has been established [69,70], suggesting that elevated PGE 2 may have an important beneficial effect for the host, despite its inhibitory effect on T cells.…”

Section: Discussionmentioning

confidence: 91%

Role of TGF‐β and PGE₂in T cell responses during Plasmodium yoelii infection

et al. 2007

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During an acute blood-stage malaria infection, T cell responses to malaria and other bystander antigens are inhibited. Plasmodium infection induces strong cytokine responses that facilitate parasite clearance but may interfere with T cell functions, as some of the soluble immune mediators induced are also general inhibitors of T cell responses. Using a malaria mouse model, we have analyzed the cytokines produced by dendritic cells in response to P. yoelii infection that have potential T cell inhibitory activity. We found that during acute infection DC migrate to the spleen and secrete TGF-b, prostaglandin E 2 (PGE 2 ) and IL-10. We have analyzed the role of these general T cell inhibitors in a particular T cell response of evident importance in malaria infections: the CD8 + T cells generated against the liver-stage of the disease. During blood-stage infection, inhibition of the activity of TGF-b and PGE 2 restores the CD8 + T cell responses generated by sporozoites, increasing protection against re-infection. Our findings suggest that the strong cytokine response induced by blood-stage P. yoelii infection affects host T cell responses, inhibiting protective CD8 + T cells against the liver-stage of the disease.

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Section: Discussionmentioning

confidence: 91%

Role of TGF‐β and PGE₂in T cell responses during Plasmodium yoelii infection

et al. 2007

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“…Africa is the continent with the highest incidence of malaria and, for example, in Uganda, the number of cases per 1000 individuals is as high as 478 (http://www.globalhealthfacts.org). Recent studies suggest that elevated plasma levels of PGE 2 in healthy children infected with malarial parasites may protect against severe clinical forms of malaria (Perkins et al, 2001(Perkins et al, , 2005. In humans, malaria is the most powerful known source of genetic selective pressure, and the frequency of polymorphic changes with malaria-protective effects is expected to be higher in affected populations (Kwiatkowski, 2005).…”

Section: Discussionmentioning

confidence: 99%

A Functional Genetic Polymorphism on Human Carbonyl Reductase 1 (CBR1V88I) Impacts on Catalytic Activity and NADPH Binding Affinity

González-Covarrubias

Ghosh²,

Lakhman³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Human carbonyl reductase 1 (CBR1) metabolizes endogenous and xenobiotic substrates such as the fever mediator, prostaglandin E2 (PGE 2 ), and the anticancer anthracycline drug, daunorubicin. We screened 33 CBR1 full-length cDNA samples from white and black liver donors and performed database analyses to identify genetic determinants of CBR1 activity. We pinpointed a single nucleotide polymorphism on CBR1 (CBR1 V88I) that encodes for a valine-toisoleucine substitution for further characterization. Human carbonyl reductase 1 (CBR1) is a monomeric cytosolic enzyme that catalyzes the two-electron reduction of biologically and pharmacologically active substrates by using NADPH as cofactor . For example, CBR1 converts the potent fever mediator prostaglandin E 2 (PGE 2 ) into the less active metabolite PGF 2␣ . Recent studies have shown that the transcription of CBR1 in lung and liver is down-regulated to suppress the catabolism of PGE 2 during the course of the febrile response (Ivanov et al., 2003;Ivanov and Romanovsky, 2004). CBR1 also plays a predominant role in the metabolism of the anticancer anthracyclines doxorubicin and daunorubicin by catalyzing the formation of their corresponding C-13 alcohol metabolites (doxorubicinol and daunorubicinol). Anthracycline C-13 alcohol metabolites circulate in plasma, have half-lives similar to those of the parent compounds, and are devoid of significant tumor cell-killing activity. The use of anthracyclines for cancer treatment is hampered by the development of clinical cardiotoxicity in some patients (Wouters et al., 2005). The pathogenesis of anthracycline-related cardiotoxicity is complex and appears to be mediated by a combination of oxidative stress and intracardiac metabolic perturbations induced by C-13 anthracycline alcohol metabolites (Minotti et al., 2004). In human myocardium, cytosolic carbonyl reductases (CBRs), and aldo/keto reductases catalyze the two-electron reduction of the anthracycline side chain C-13 carbonyl group to form cardiotoxic alcohol metabolites (e.g., doxorubicinol, daunorubicinol). CBR activity is the main source of quinone detoxification in humans, and biochemical studies showed that aldo/keto reductases have 7-to 18-fold lower catalytic efficiencies (V max /K m ) for the reduction of anthracycline substrates than CBRs (Wermuth et al., 1986;Ohara et al., 1995;Rosemond and Walsh, 2004;Covarrubias et al., 2006). The key role of CBR1 during the pathogenesis of anthracycline-related cardiotoxicity has been established in biochemical studies and in experiments with murine models (Mordente et al., 2001). Mice overexpressing human CBR1 in heart showed high intracardiac levels of doxorubicinol and increased signs of myocardial damage after doxorubicin administration . Conversely, mice with a

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“…Our previous study of children with MA and/or hyperparasitemia showed that plasma bicyclo-PGE 2 levels and PBMC COX-2 gene expression are suppressed during acute malaria, with the lowest levels of COX-2 and PGE 2 associated with the most severe cases of disease [10]. It has also been shown that reduced urinary concentrations of bicyclo-PGE 2 are associated with adverse neurological sequelae and death among children with cerebral malaria [37], and that increasing pfHz deposition in cultured intervillous blood mononuclear cells obtained from women with placental malaria is correlated with decreased PGE 2 biosynthesis [38]. Additional studies performed in our laboratory confirmed that phagocytosis of pfHz by stimulated human PBMCs is responsible, at least in part, for decreased COX-2-derived PGE 2 biosynthesis during malaria [11].…”

Section: Discussionmentioning

confidence: 99%

Suppression of Prostaglandin E₂by Malaria Parasite Products and Antipyretics Promotes Overproduction of Tumor Necrosis Factor–α: Association with the Pathogenesis of Childhood Malarial Anemia

et al. 2006

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Cytokines and effector molecules are important immunoregulatory molecules in human malaria. Tumor necrosis factor (TNF)-a limits malaria parasitemia but also promotes pathogenesis at high concentrations, whereas prostaglandin E 2 (PGE 2 ) inhibits TNF-a production and is reduced in childhood malaria, at least in part, through suppression of cyclooxygenase (COX)-2 following the ingestion of Plasmodium falciparum hemozoin (pfHz; malarial pigment) by peripheral blood mononuclear cells (PBMCs). Although molecular interactions between TNF-a and PGE 2 are largely unexplored in human malaria, results presented here show that pfHz-induced suppression of PBMC COX-2 gene products induces overproduction of TNF-a. Moreover, addition of exogenous PGE 2 to pfHz-treated PBMCs dose-dependently decreased TNF-a production, whereas experimental COX inhibitors and antipyretics used during human malaria generated increased TNF-a production. Healthy, malariaexposed children had elevated levels of circulating bicyclo-PGE 2 /TNF-a, compared with children with malarial anemia ( ), with systemic bicyclo-PGE 2 and TNF-a significantly associated with hemoglobin concentrations P ! .01 ( ; ). The results of the present study illustrate that pfHz-induced suppression of PGE 2 promotes r p 0.745 P ! .01 overproduction of TNF-a, which is associated with enhanced malarial anemia.Malarial anemia (MA) is a multifaceted clinical manifestation of malaria that has varying etiologies, including intravascular and extravascular hemolysis of infected and noninfected red blood cells (RBCs), as well as suppression of erythropoiesis [1]. In Gabon, a hyperendemic Plasmodium falciparum malaria transmission area, the primary clinical manifestations of severe childhood malaria are severe anemia and/or hyperpar-

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Impaired Systemic Production of Prostaglandin E₂in Children with Cerebral Malaria

Cited by 21 publications

References 40 publications

Role of TGF‐β and PGE₂in T cell responses during Plasmodium yoelii infection

Role of TGF‐β and PGE₂in T cell responses during Plasmodium yoelii infection

A Functional Genetic Polymorphism on Human Carbonyl Reductase 1 (CBR1V88I) Impacts on Catalytic Activity and NADPH Binding Affinity

Suppression of Prostaglandin E₂by Malaria Parasite Products and Antipyretics Promotes Overproduction of Tumor Necrosis Factor–α: Association with the Pathogenesis of Childhood Malarial Anemia

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Impaired Systemic Production of Prostaglandin E2in Children with Cerebral Malaria

Cited by 21 publications

References 40 publications

Role of TGF‐β and PGE2 in T cell responses during Plasmodium yoelii infection

Role of TGF‐β and PGE2 in T cell responses during Plasmodium yoelii infection

A Functional Genetic Polymorphism on Human Carbonyl Reductase 1 (CBR1V88I) Impacts on Catalytic Activity and NADPH Binding Affinity

Suppression of Prostaglandin E2by Malaria Parasite Products and Antipyretics Promotes Overproduction of Tumor Necrosis Factor–α: Association with the Pathogenesis of Childhood Malarial Anemia

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Impaired Systemic Production of Prostaglandin E₂in Children with Cerebral Malaria

Role of TGF‐β and PGE₂in T cell responses during Plasmodium yoelii infection

Role of TGF‐β and PGE₂in T cell responses during Plasmodium yoelii infection

Suppression of Prostaglandin E₂by Malaria Parasite Products and Antipyretics Promotes Overproduction of Tumor Necrosis Factor–α: Association with the Pathogenesis of Childhood Malarial Anemia