title: 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.
abstract: 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-alpha) 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-alpha 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-alpha by altering the transcriptional kinetics of IL-12p40, IL-10, and TNF-alpha, respectively. IL-10 neutralizing antibodies, but not TNF-alpha 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.
authors.affiliation: University of Pittsburgh Graduate School of Public Health, Department of Infectious Diseases and Microbiology, 130 DeSoto Street, 603 Parran Hall, Pittsburgh, PA 15261, USA.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Keller
authors.forename: Ouma
authors.initials: O
authors.lastname: Yamo
authors.forename: Collins
authors.initials: C
authors.lastname: Ouma
authors.forename: John Michael
authors.initials: JM
authors.lastname: Ong'echa
authors.forename: David
authors.initials: D
authors.lastname: Ounah
authors.forename: James B
authors.initials: JB
authors.lastname: Hittner
authors.forename: John M
authors.initials: JM
authors.lastname: Vulule
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Perkins
mesh_terms: D000740:Anemia / Q000235:genetics / Q000276:immunology / Q000469:parasitology*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002478:Cells, Cultured; D002675:Child, Preschool; D015536:Down-Regulation; D005260:Female; D006420:Hemeproteins / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D018664:Interleukin-12 / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D053762:Interleukin-12 Subunit p40; D018950:Lipopolysaccharide Receptors / Q000032:analysis; D016778:Malaria, Falciparum / Q000235:genetics / Q000276:immunology*; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D010587:Phagocytosis; D010963:Plasmodium falciparum; D021122:Protein Subunits / Q000235:genetics*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000906:Antibodies; D006420:Hemeproteins; D053762:Interleukin-12 Subunit p40; D018950:Lipopolysaccharide Receptors; D021122:Protein Subunits; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; C020753:hemozoin