title: Macrophage preconditioning with synthetic malaria pigment reduces cytokine production via heme iron-dependent oxidative stress.
abstract: Hemozoin (malaria pigment), a polymer of hematin (ferri-protoporphyrin IX) derived from hemoglobin ingested by intraerythrocytic plasmodia, modulates cytokine production by phagocytes. Mouse peritoneal macrophages (PM) fed with synthetic beta-hematin (BH), structurally identical to native hemozoin, no longer produce tumor necrosis factor alpha (TNFalpha) and nitric oxide (NO) in response to lipopolysaccharide (LPS). Impairment of NO synthesis is due to inhibition of inducible nitric oxide synthase (iNOS) production. BH-mediated inhibition of PM functions cannot be ascribed to iron release from BH because neither prevention by iron chelators nor down-regulation of iron-regulatory protein activity was detected. Inhibition appears to be related to pigment-induced oxidative stress because (a) thiol compounds partially restored PM functions, (b) heme oxygenase (HO-1) and catalase mRNA levels were up-regulated, and (c) free radicals production increased in BH-treated cells. The antioxidant defenses of the cells determine the response to BH: microglia cells, which show a lower extent of induction of HO-1 and catalase mRNAs and lower accumulation of oxygen radicals, are less sensitive to the inhibitory effect of BH on cytokine production. Results indicate that BH is resistant to degradation by HO-1 and that heme-iron mediated oxidative stress may contribute to malaria-induced immunosuppression. This study may help correlate the different clinical manifestations of malaria, ranging from uncomplicated to severe disease, with dysregulation of phagocyte functions and promote better therapeutic strategies to counteract the effects of hemozoin accumulation.
authors.affiliation: Istituto di Microbiologia, Università di Milano, Milan, Italy. donatella.taramelli@unimi.it
authors.forename: D
authors.initials: D
authors.lastname: Taramelli
authors.forename: S
authors.initials: S
authors.lastname: Recalcati
authors.forename: N
authors.initials: N
authors.lastname: Basilico
authors.forename: P
authors.initials: P
authors.lastname: Olliaro
authors.forename: G
authors.initials: G
authors.lastname: Cairo
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D004790:Enzyme Induction; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis; D051547:Heme Oxygenase-1; D006420:Hemeproteins / Q000494:pharmacology*; D006427:Hemin / Q000494:pharmacology; D007501:Iron / Q000494:pharmacology; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins / Q000032:analysis; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D008565:Membrane Proteins; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000502:physiology; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D018384:Oxidative Stress; D010860:Pigments, Biological / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000032:analysis; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D005609:Free Radicals; D006420:Hemeproteins; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D010860:Pigments, Biological; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C020753:hemozoin; D006427:Hemin; D007501:Iron; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse