Abstract
Acute and chronic Plasmodium falciparum malaria are accompanied by severe immunodepression possibly related to subversion of dendritic cells (DC) functionality. Phagocytosed hemozoin (malarial pigment) was shown to inhibit monocyte functions related to immunity. Hemozoin-loaded monocytes, frequently found in circulation and adherent to endothelia in malaria, may interfere with DC development and play a role in immunodepression. Hemozoin-loaded and unloaded human monocytes were differentiated in vitro to immature DC (iDC) by treatment with GM-CSF and IL-4, and to mature DC (mDC) by LPS challenge. In a second setting, hemozoin was fed to iDC further cultured to give mDC. In both settings, cells ingested large amounts of hemozoin undegraded during DC maturation. Hemozoin-fed monocytes did not apoptose but their differentiation and maturation to DC was severely impaired as shown by blunted expression of MHC class II and costimulatory molecules CD83, CD80, CD54, CD40, CD1a, and lower levels of CD83-specific mRNA in hemozoin-loaded iDC and mDC compared with unfed or latex-loaded DC. Further studies indicated activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) in hemozoin-loaded iDC and mDC, associated with increased expression of PPAR-gamma mRNA, without apparent involvement of NF-kappaB. Moreover, expression of PPAR-gamma was induced and up-regulation of CD83 was inhibited by supplementing iDC and mDC with plausible concentrations of 15(S)-hydroxyeicosatetraenoic acid, a PPAR-gamma ligand abundantly produced by hemozoin via heme-catalyzed lipoperoxidation.
Copyright 2004 The American Association of Immunologists, Inc.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aldehydes / metabolism
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Aldehydes / pharmacology
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Animals
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Antigens, CD
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Antigens, CD1 / biosynthesis
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Antigens, Surface / biosynthesis
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Apoptosis / immunology
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Biotransformation
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CD83 Antigen
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Cell Differentiation / immunology
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Dendritic Cells / parasitology
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Dendritic Cells / pathology
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Growth Inhibitors / metabolism
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Growth Inhibitors / pharmacology
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Growth Inhibitors / physiology*
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Hemeproteins / metabolism
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Hemeproteins / physiology*
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Humans
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Hydroxyeicosatetraenoic Acids / metabolism
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Hydroxyeicosatetraenoic Acids / physiology
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Immunoglobulins / biosynthesis
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Immunoglobulins / genetics
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Immunosuppressive Agents / metabolism
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Immunosuppressive Agents / pharmacology*
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Leukocyte Count
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Ligands
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Membrane Glycoproteins / antagonists & inhibitors
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Membrane Glycoproteins / biosynthesis
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Membrane Glycoproteins / genetics
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Monocytes / immunology*
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Monocytes / metabolism
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Monocytes / parasitology
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Monocytes / pathology
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NF-kappa B / metabolism
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Peroxisomes / immunology
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Peroxisomes / metabolism
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Peroxisomes / parasitology
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Peroxisomes / pathology
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Phagocytosis / immunology
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Pigments, Biological / metabolism
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Pigments, Biological / physiology*
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Plasmodium falciparum / immunology*
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RNA, Messenger / antagonists & inhibitors
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RNA, Messenger / biosynthesis
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Receptors, Cytoplasmic and Nuclear / biosynthesis
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Cytoplasmic and Nuclear / metabolism
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Receptors, Cytoplasmic and Nuclear / physiology*
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Transcription Factors / biosynthesis
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription Factors / physiology*
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Up-Regulation / immunology
Substances
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Aldehydes
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Antigens, CD
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Antigens, CD1
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Antigens, Surface
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CD1a antigen
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Growth Inhibitors
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Hemeproteins
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Hydroxyeicosatetraenoic Acids
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Immunoglobulins
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Immunosuppressive Agents
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Ligands
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Membrane Glycoproteins
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NF-kappa B
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Pigments, Biological
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RNA, Messenger
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Receptors, Cytoplasmic and Nuclear
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Transcription Factors
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hemozoin
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15-hydroxy-5,8,11,13-eicosatetraenoic acid
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4-hydroxy-2-nonenal