Suppression of Macrophage Migration Inhibitory Factor in Children with Severe Malarial Anemia: Role of Monocyte-acquired Hemozoin
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Publication Date
2006Author
Gordon A Awandare, Yamo Ouma, Collins Ouma, Tom Were, Richard Otieno, Christopher C Keller, Gregory C Davenport, James B Hittner, John Vulule, Robert Ferrell, John M Ong'echa, Douglas J Perkins
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Severe malarial anemia (SMA), caused by Plasmodium falciparum infections, is one of the
leading causes of childhood mortality in sub-Saharan Africa. Although the molecular
determinants of SMA are largely undefined, dysregulation in host-derived inflammatory
mediators influences disease severity. Macrophage migration inhibitory factor (MIF) is an
important regulator of innate inflammatory responses that has recently been shown to suppress
erythropoiesis and promote pathogenesis of SMA in murine models. To examine the role of
MIF in the development of childhood SMA, peripheral blood MIF production was examined in
Kenyan children (aged <3 years, n=357) with P. falciparum malarial anemia. All children in the
study were free from bacteremia and HIV-1. Since deposition of malarial pigment (hemozoin)
contributes to suppression of erythropoiesis, the relationship between MIF concentrations and
monocytic acquisition of Hz was also examined in vivo and in vitro. Circulating MIF
concentrations declined with increasing severity of anemia and significantly correlated with
peripheral blood leukocyte MIF transcripts. However, MIF concentrations in peripheral blood
were not significantly associated with reticulocyte production. Multivariate regression analyses,
controlling for age, gender and parasitemia, further revealed that elevated levels of pigmentcontaining monocytes (PCM) was associated with SMA and decreased MIF production. In
addition, PCM levels were a better predictor of hemoglobin and MIF concentrations than
parasite density. Additional experiments in malaria-naïve individuals demonstrated that
hemozoin caused both increased and decreased MIF production in cultured peripheral blood
mononuclear cells (PBMC) in a donor-specific manner, independent of apoptosis. However,
PBMC MIF production in children with acute malaria progressively declined with increasing
anemia severity. Results presented here demonstrate that acquisition of hemozoin by
monocytes is associated with suppression of peripheral blood MIF production and enhanced
severity of anemia in childhood malaria.
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