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Infection and Immunity, September 2006, p. 5249-5260, Vol. 74, No. 9
0019-9567/06/$08.00+0     doi:10.1128/IAI.00843-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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

Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania,¹ Lake Erie College of Osteopathic Medicine, Erie, Pennsylvania,² University of Pittsburgh/KEMRI Laboratories of Parasitic and Viral Diseases, Center for Vector Biology and Control Research, Kenya Medical Research Institute, Kisumu, Kenya,³ Department of Biological Sciences, Kenyatta University, Nairobi, Kenya,⁴ Department of Psychology, College of Charleston, Charleston, South Carolina,⁵ Centre for Vector Biology and Control Research, Kenya Medical Research Institute, Kisumu, Kenya⁶

Received 25 May 2006/ Returned for modification 3 June 2006/ Accepted 18 June 2006

Severe malarial anemia (SMA) is a primary cause of morbidity and mortality in immune-naïve infants and young children residing in areas of holoendemic Plasmodium falciparum transmission. Although the immunopathogenesis of SMA is largely undefined, we have previously shown that systemic interleukin-12 (IL-12) production is suppressed during childhood blood-stage malaria. Since IL-10 and tumor necrosis factor alpha (TNF-) are known to decrease IL-12 synthesis in a number of infectious diseases, altered transcriptional regulation of these inflammatory mediators was investigated as a potential mechanism for IL-12 down-regulation. Ingestion of naturally acquired malarial pigment (hemozoin [PfHz]) by monocytes promoted the overproduction of IL-10 and TNF- relative to the production of IL-12, which correlated with an enhanced severity of malarial anemia. Experiments with cultured peripheral blood mononuclear cells (PBMC) and CD14⁺ cells from malaria-naïve donors revealed that physiological concentrations of PfHz suppressed IL-12 and augmented IL-10 and TNF- by altering the transcriptional kinetics of IL-12p40, IL-10, and TNF-, respectively. IL-10 neutralizing antibodies, but not TNF- antibodies, restored PfHz-induced suppression of IL-12. Blockade of IL-10 and the addition of recombinant IL-10 to cultured PBMC from children with SMA confirmed that IL-10 was responsible for malaria-induced suppression of IL-12. Taken together, these results demonstrate that PfHz-induced up-regulation of IL-10 is responsible for the suppression of IL-12 during malaria.

Editor: W. A. Petri, Jr.

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