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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.

Original publication

DOI

10.1038/labinvest.3780189

Type

Journal article

Journal

Laboratory investigation; a journal of technical methods and pathology

Publication Date

12/2000

Volume

80

Pages

1781 - 1788

Addresses

Istituto di Microbiologia, Università di Milano, Milan, Italy. donatella.taramelli@unimi.it

Keywords

Microglia, Cells, Cultured, Cell Line, Macrophages, Peritoneal, Animals, Mice, Iron, Free Radicals, Nitric Oxide, Hemin, Heme Oxygenase (Decyclizing), Lipopolysaccharides, Tumor Necrosis Factor-alpha, Iron-Sulfur Proteins, RNA-Binding Proteins, Hemeproteins, Iron-Regulatory Proteins, Membrane Proteins, Recombinant Proteins, Cell Survival, Enzyme Induction, Oxidative Stress, Female, Pigments, Biological, Nitric Oxide Synthase, Heme Oxygenase-1, Nitric Oxide Synthase Type II