Acquisition of Hemozoin by Monocytes Down-Regulates Interleukin-12 p40 (IL-12p40) Transcripts and Circulating IL-12p70 through an IL-10-Dependent Mechanism: In Vivo and In Vitro Findings in Severe Malarial Anemia

Keller, Christopher; Ouma, Yamo; Ouma, Collins; Ong’echa, John Michael; Ounah, David; Hittner, James B.; Vulule, John; Perkins, Douglas J

doi:10.1128/iai.00843-06

Cited by 74 publications

(90 citation statements)

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“…Although IL-23 and IL-12 share the p40 subunit [17], levels of IL-23 were elevated in children with malarial anemia, while plasma IL-12 concentrations progressively declined with increasing anemia severity. The decrease in IL-12 with increasing disease severity parallels previous findings in African children residing in areas with intense malaria transmission [12][13][14]29,[43][44][45]. In addition, examination of the IL-12 to IL-23 ratio revealed that SMA is characterized by low levels of IL-12 relative to IL-23.…”

Section: Discussionsupporting

confidence: 82%

“…Results presented here showing that the relative expression of IL-10 to IL-23 progressively increased with increasing anemia severity may suggest that IL-10 could have a suppressive effect on IL-23 production. Our previous investigations illustrate that phagocytosis of malarial pigment by monocytes causes enhanced production of IL-10 that, in turn, suppresses IL-12 [29]. These results have important implications in the pathogenesis of malarial anemia since IL-12 is required for promotion of erythropoiesis through its ability to enhance erythroid burst (BFU-E) and colony forming units (CFU-E) [47,48].…”

Section: Discussionmentioning

confidence: 96%

“…Previous investigations from our laboratory illustrate that phagocytosis of malarial pigment (hemozoin, Hz) by cultured human peripheral blood mononuclear cells (PBMC) generates a profile of cytokine production similar to that observed in children with malarial anemia [27][28][29]. Hz is a Plasmodium-derived biomineralized product of heme, a prosthetic group of hemoglobin (Hb) liberated during Hb degradation [30].…”

Section: Introductionmentioning

confidence: 85%

“…PBMC were isolated using Ficoll-Hypaque and plated at a density of 1 × 10 6 cells/mL in Dulbecco's Modified Eagle Medium (DMEM) containing 10% pooled human sera (heat-inactivated at 56°C for 30 min) according to our previous methods [29,38]. Cultures were stimulated with media alone (controls) or β-hematin (synthetic Hz, sHz; 10 μg/ mL).…”

Section: Pbmc Isolation and Culturementioning

confidence: 99%

“…We have previously shown that parasite-derived products, such as pfHz, cause dysregulation of de novo cytokine transcription in cultured PBMC [27][28][29]38]. IL-23 and IL-12 share the IL-12p40 subunit [17] and are both antagonized by IL-10 [22,23] and secreted forms of IL-12p40 [20,24].…”

Section: Effect Of Shz On Pbmc Cytokine Gene Expressionmentioning

confidence: 99%

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Increased circulating interleukin (IL)-23 in children with malarial anemia: In vivo and in vitro relationship with co-regulatory cytokines IL-12 and IL-10

Ong’echa

Remo

Kristoff

et al. 2008

Clinical Immunology

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Severe malarial anemia (SMA) is a leading cause of mortality among children in sub-Saharan Africa. Although the novel cytokine, interleukin (IL)-23, promotes anemia in chronic inflammatory diseases, the role of IL-23 in SMA remains undefined. Since IL-23 and IL-12 share the IL-12p40 subunit and IL-12Rβ1 receptor, and are down-regulated by IL-10, relationships among these cytokines were explored in Kenyan children with varying severities of malarial anemia. Children with malarial anemia had increased circulating IL-23 and IL-10, and decreased IL-12 relative to healthy controls. Enhanced anemia severity and elevated parasitemia were associated with increased IL-10 relative to IL-23 and IL-12. Further exploration of the relationships among the cytokines using an in vitro model in which peripheral blood mononuclear cells were treated with synthetic hemozoin (sHz, malarial pigment) revealed that IL-12p35 and IL-23p19 transcripts had a sustained induction over 72 hrs, while IL-12p40 and IL-10 message peaked at 24 hrs, and rapidly declined thereafter. Taken together, results here show that IL-23 is elevated in children with malarial anemia, and that IL-10 and IL-12 appear to have important regulatory effects on IL-23 production during childhood malaria.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 85%

Section: Pbmc Isolation and Culturementioning

confidence: 99%

Section: Effect Of Shz On Pbmc Cytokine Gene Expressionmentioning

confidence: 99%

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Increased circulating interleukin (IL)-23 in children with malarial anemia: In vivo and in vitro relationship with co-regulatory cytokines IL-12 and IL-10

Ong’echa

Remo

Kristoff

et al. 2008

Clinical Immunology

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Hematological predictors of increased severe anemia in Kenyan children coinfected with Plasmodium falciparum and HIV‐1

et al. 2010

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Malaria and HIV‐1 are coendemic in many developing countries, with anemia being the most common pediatric hematological manifestation of each disease. Anemia is also one of the primary causes of mortality in children monoinfected with either malaria or HIV‐1. Although our previous results showed HIV‐1(+) children with acute Plasmodium falciparum malaria [Pf(+)] have more profound anemia, potential causes of severe anemia in coinfected children remain unknown. As such, children with P. falciparum malaria (aged 3–36 months, n = 542) from a holoendemic malaria transmission area of western Kenya were stratified into three groups: HIV‐1 negative [HIV‐1(−)/Pf(+)]; HIV‐1 exposed [HIV‐1(exp)/Pf(+)]; and HIV‐1 infected [HIV‐1(+)/Pf(+)]. Comprehensive clinical, parasitological, and hematological measures were determined upon enrollment. Univariate, correlational, and hierarchical regression analyses were used to determine differences among the groups and to define predictors of worsening anemia. HIV‐1(+)/Pf(+) children had significantly more malarial pigment‐containing neutrophils (PCN), monocytosis, increased severe anemia (Hb < 6.0 g/dL), and nearly 10‐fold greater mortality within 3 months of enrollment. Common causes of anemia in malaria‐infected children, such as increased parasitemia or reduced erythropoiesis, did not account for worsening anemia in the HIV‐1(+)/Pf(+) group nor did carriage of sickle cell trait or G6PD deficiency. Hierarchical multiple regression analysis revealed that more profound anemia was associated with elevated PCM, younger age, and increasing HIV‐1 status ([HIV‐1(−) → HIV‐1(exp) → HIV‐1(+)]. Thus, malaria/HIV‐1 coinfection is characterized by more profound anemia and increased mortality, with acquisition of monocytic pigment having the most detrimental impact on Hb levels. Am. J. Hematol., 2010. © 2010 Wiley‐Liss, Inc.

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Mechanisms of erythropoiesis inhibition by malarial pigment and malaria‐induced proinflammatory mediators in an in vitro model

et al. 2011

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One of the commonest complications of Plasmodium falciparum malaria is the development of severe malarial anemia (SMA), which is, at least in part, due to malaria-induced suppression of erythropoiesis. Factors associated with suppression of erythropoiesis and development of SMA include accumulation of malarial pigment (hemozoin, PfHz) in bone marrow and altered production of inflammatory mediators, such as tumor necrosis factor (TNF)-α, and nitric oxide (NO). However, studies investigating the specific mechanisms responsible for inhibition of red blood cell development have been hampered by difficulties in obtaining bone marrow aspirates from infants and young children, and the lack of reliable models for examining erythroid development. As such, an in vitro model of erythropoiesis was developed using CD34+ stem cells derived from peripheral blood to examine the effects of PfHz, PfHz-stimulated peripheral blood mononuclear cell (PBMC)-conditioned media (CM-PfHz), TNF-α, and NO on erythroid cell development. PfHz only slightly suppressed erythroid cell proliferation and maturation marked by decreased expression of glycophorin A (GPA). On the other hand, CM-PfHz, TNF-α, and NO significantly inhibited erythroid cell proliferation. Furthermore, decreased proliferation in cells treated with CM-PfHz and NO was accompanied by increased apoptosis of erythropoietin-stimulated CD34+ cells. In addition, NO significantly inhibited erythroid cell maturation, whereas TNF-α did not appear to be detrimental to maturation. Collectively, our results demonstrate that PfHz suppresses erythropoiesis by acting both directly on erythroid cells, and indirectly via inflammatory mediators produced from PfHz-stimulated PBMC, including TNF-α and NO.

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Acquisition of Hemozoin by Monocytes Down-Regulates Interleukin-12 p40 (IL-12p40) Transcripts and Circulating IL-12p70 through an IL-10-Dependent Mechanism: In Vivo and In Vitro Findings in Severe Malarial Anemia

Cited by 74 publications

References 50 publications

Increased circulating interleukin (IL)-23 in children with malarial anemia: In vivo and in vitro relationship with co-regulatory cytokines IL-12 and IL-10

Increased circulating interleukin (IL)-23 in children with malarial anemia: In vivo and in vitro relationship with co-regulatory cytokines IL-12 and IL-10

Hematological predictors of increased severe anemia in Kenyan children coinfected with Plasmodium falciparum and HIV‐1

Mechanisms of erythropoiesis inhibition by malarial pigment and malaria‐induced proinflammatory mediators in an in vitro model

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