title: Role of the NF-κB transcription pathway in the haemozoin- and 15-HETE-mediated activation of matrix metalloproteinase-9 in human adherent monocytes.
abstract: Haemozoin (HZ, malarial pigment) is a crystalline ferriprotoporphyrin IX polymer derived from undigested host haemoglobin haem, present in late stages of Plasmodium falciparum-parasitized RBCs and in residual bodies shed after schizogony. It was shown previously that phagocytosed HZ or HZ-containing trophozoites increased monocyte matrix metalloproteinase-9 (MMP-9) activity and enhanced production of MMP-9-related cytokines TNF and IL-1beta. Here we show that in human monocytes the HZ/trophozoite phagocytosis effects and their recapitulation by 15(S,R)-hydroxy-6,8,11,13-eicosatetraenoic acid (15-HETE), a potent lipoperoxidation derivative generated by HZ from arachidonic acid via haem catalysis, were mediated via activation of NF-κB transcription pathway. After phagocytosis of HZ/trophozoites or treatment with 15-HETE, the NF-κB complex migrated to the nuclear fraction while the inhibitory cytosolic IκBalpha protein was phosphorylated and degraded. All HZ/trophozoite/15-HETE effects on MMP-9 activity and TNF/IL-1beta production were abrogated by quercetin, artemisinin and parthenolide, inhibitors of IκBalpha phosphorylation and subsequent degradation, NF-κB nuclear translocation, and NF-κB-p65 binding to DNA respectively. In conclusion, enhanced activation of MMP-9, and release of pro-inflammatory cytokines TNF and IL-1beta, a triad of effects involved in malaria pathogenesis, elicited in human monocytes by trophozoite and HZ phagocytosis and recapitulated by 15-HETE, appear to be causally connected to persisting activation of the NF-κB system.
authors.affiliation: Dipartimento di Genetica, Biologia e Biochimica, Università di Torino, Via Santena 5 bis, 10126 Torino, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Prato
authors.forename: Valentina
authors.initials: V
authors.lastname: Gallo
authors.forename: Giuliana
authors.initials: G
authors.lastname: Giribaldi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Aldieri
authors.forename: Paolo
authors.initials: P
authors.lastname: Arese
mesh_terms: D005786:Gene Expression Regulation; D006420:Hemeproteins / Q000378:metabolism*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000469:parasitology; D016328:NF-kappa B / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000276:immunology*; D015398:Signal Transduction; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D006420:Hemeproteins; D006893:Hydroxyeicosatetraenoic Acids; D053583:Interleukin-1beta; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C020753:hemozoin; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D020780:Matrix Metalloproteinase 9