title: Phagocytosis of hemozoin enhances matrix metalloproteinase-9 activity and TNF-alpha production in human monocytes: role of matrix metalloproteinases in the pathogenesis of falciparum malaria.
abstract: Matrix metalloproteinase-9 (MMP-9), secreted by activated monocytes, degrades matrix proteins, disrupts basal lamina, and activates TNF-alpha from its precursors. In turn, TNF-alpha enhances synthesis of MMP-9 in monocytes. We show here that trophozoite-parasitized RBCs/hemozoin-fed adherent human monocytes displayed increased MMP-9 activity and protein/mRNA expression, produced TNF-alpha time-dependently, and showed higher matrix invasion ability. MMP-9 activation was specific for trophozoite/hemozoin-fed monocytes, was dependent on TNF-alpha production, and abrogated by anti-TNF-alpha Ab and by a specific inhibitor of MMP-9/MMP-13 activity. Hemozoin-induced enhancement of MMP-9 and TNF-alpha production would have a 2-fold effect: to start and feed a cyclic reinforcement loop in which hemozoin enhances production of TNF-alpha, which in turn induces both activation of MMP-9 and shedding of TNF-alpha into the extracellular compartment; and, second, to disrupt the basal lamina of endothelia. Excess production of TNF-alpha and disruption of the basal lamina with extravasation of blood cells into perivascular tissues are hallmarks of severe malaria. Pharmacological inhibition of MMP-9 may offer a new chance to control pathogenic mechanisms in malaria.
authors.affiliation: Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Prato
authors.forename: Giuliana
authors.initials: G
authors.lastname: Giribaldi
authors.forename: Manuela
authors.initials: M
authors.lastname: Polimeni
authors.forename: Valentina
authors.initials: V
authors.lastname: Gallo
authors.forename: Paolo
authors.initials: P
authors.lastname: Arese
mesh_terms: D000818:Animals; D001483:Base Sequence; D015801:Helminth Proteins / Q000276:immunology*; D006420:Hemeproteins / Q000276:immunology*; D006801:Humans; D066298:In Vitro Techniques; D016778:Malaria, Falciparum / Q000201:enzymology* / Q000235:genetics / Q000276:immunology* / Q000469:parasitology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology* / Q000469:parasitology; D010587:Phagocytosis; D010860:Pigments, Biological; D010963:Plasmodium falciparum / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000494:pharmacology
chemical_list: D015801:Helminth Proteins; D006420:Hemeproteins; D010860:Pigments, Biological; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C020753:hemozoin; D020780:Matrix Metalloproteinase 9