期刊
CELLULAR MICROBIOLOGY
卷 12, 期 12, 页码 1780-1791出版社
WILEY
DOI: 10.1111/j.1462-5822.2010.01508.x
关键词
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资金
- Compagnia di San Paolo, Torino, Italian Malaria Network
- Regione Piemonte, Ricerca Sanitaria Finalizzata
P>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-kappa B transcription pathway. After phagocytosis of HZ/trophozoites or treatment with 15-HETE, the NF-kappa B complex migrated to the nuclear fraction while the inhibitory cytosolic I kappa Balpha 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 I kappa Balpha phosphorylation and subsequent degradation, NF-kappa B nuclear translocation, and NF-kappa B-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-kappa B system.
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