The heme moiety of malaria pigment (beta-hematin) mediates the inhibition of nitric oxide and tumor necrosis factor-alpha production by lipopolysaccharide-stimulated macrophages.
To investigate the effect of the heme moiety of malaria pigment, hemozoin, on phagocyte functions, mouse macrophages were fed with insoluble beta-hematin, the synthetic heme-polymer chemically identical to the native pigment, or the soluble monomer, hematin. Production of inflammatory cytokines, interleukin 1 (IL1), tumor necrosis factor alpha (TNF alpha), and nitric oxide (NO) was assayed in the supernatants after stimulation with lipopolysaccharide. The results indicate that both beta-hematin and hematin induce a dose-dependent inhibition of macrophage production of TNF alpha and NO, but not of IL1. One-hour pretreatment with soluble hematin inhibited production of cytotoxic mediators by more than 50% compared to controls, while 6-hr exposure was necessary for insoluble beta-hematin to induce the same level of inhibition. However, the same treatment did not modify the production of TNF alpha and NO by mouse microglia cell lines. The inhibition was partially counterbalanced by adding sulphydryl group donors such as 2-mercaptoethanol, glutathione, or N-acetyl-cysteine during the preincubation time. The results of the present study confirm the inhibitory role of malaria pigment and show that such effect is due to the heme moiety and may be selective for the production of cytotoxic mediators by specific phagocytes. The implications of these findings in the control of malaria infection and disease and in the pathogenesis of severe malaria are discussed.
Istituto di Microbiologia Medica, Universitá di Milano, Italy.
D
D
Taramelli
N
N
Basilico
E
E
Pagani
R
R
Grande
D
D
Monti
M
M
Ghione
P
P
Olliaro
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D006418:Heme / Q000494:pharmacology*; D006420:Hemeproteins / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D008288:Malaria / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000187:drug effects; D009569:Nitric Oxide / Q000096:biosynthesis*; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D006420:Hemeproteins; D008070:Lipopolysaccharides; D013438:Sulfhydryl Compounds; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C020753:hemozoin; D006418:Heme