Open AccessRole of the NF‐κB transcription pathway in the haemozoin‐ and 15‐HETE‐mediated activation of matrix metalloproteinase‐9 in human adherent monocytes
Author(s) -
Prato Mauro,
Gallo Valentina,
Giribaldi Giuliana,
Aldieri Elisabetta,
Arese Paolo
Publication year - 2010
Publication title -
cellular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.542
H-Index - 138
eISSN - 1462-5822
pISSN - 1462-5814
DOI - 10.1111/j.1462-5822.2010.01508.x
Subject(s) - biology , phagocytosis , microbiology and biotechnology , matrix metalloproteinase , monocyte , cytosol , proinflammatory cytokine , transcription (linguistics) , nf κb , tumor necrosis factor alpha , phosphorylation , signal transduction , inflammation , biochemistry , immunology , enzyme , linguistics , philosophy
Summary 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.