Over-regulated production of pro-inflammatory molecules is a typical feature of complicated malaria. Of note, IL-1beta seems to play a key role in coma development during cerebral malaria (CM), an encephalopathy characterized by sequestration of parasitized red blood cells in brain microvessels, thrombosis, local inflammation, blood-brain barrier leakage and in some cases extravasation of non-apoptotic monocytes frequently laden with malarial pigment haemozoin (HZ), a lipid-enriched ferriprotoporphyrin IX crystal produced by Plasmodium falciparum after haemoglobin catabolism. In the present work the effects of HZ on IL-1beta regulation in human monocytes were studied. Results showed that phagocytosis of natural HZ promoted praecox mRNA expression and following protein release of IL-1beta. Such an enhancement was dependent on the lipid moiety of HZ, since lipid-free synthetic and delipidized natural HZ did not reproduce these effects. 15(S,R)-hydroxy-6,8,11,13-eicosatetraenoic acid (15-HETE), a potent lipoperoxidation derivative generated by HZ from arachidonic acid through haem-catalysis, mimicked the HZ effects on IL-1beta. Moreover SB203580, a synthetic p38 inhibitor, as well as quercetin, artemisinin and parthenolide, three NF-kappaB inhibitors with antimalarial properties, abrogated either HZ- or 15-HETE-dependent enhancement of IL-1beta. Interestingly, experiments with anti-IL-1beta blocking antibodies or recombinant IL-1beta showed that over-regulated IL-1beta was causally connected to the HZ-dependent enhancement of mRNA expression and protein release of Matrix Metalloproteinase-9 (MMP-9) and Tissue Inhibitor of Metalloproteinase-1 (TIMP-1), two molecules involved in blood-brain barrier damage, activation of cytokine proforms, haemostasis and cell survival. Taken altogether, the present data suggest that in human monocytes the lipid moiety of HZ promotes IL-1beta production trough either p38- or NF-kappaB-dependent mechanisms, and a role for 15-HETE is likely; as a consequence, IL-1beta enhances MMP-9 and TIMP-1, possibly favouring the clinical progress towards CM.
Phagocytosis of malarial pigment promotes IL-1beta production in human monocytes: possible role in clinical progress towards complicated malaria
GIRIBALDI, Giuliana;POLIMENI, Manuela;VALENTE, Elena;KHADJAVI, AMINA;ULLIERS, Daniela;PRATO, Mauro
2011-01-01
Abstract
Over-regulated production of pro-inflammatory molecules is a typical feature of complicated malaria. Of note, IL-1beta seems to play a key role in coma development during cerebral malaria (CM), an encephalopathy characterized by sequestration of parasitized red blood cells in brain microvessels, thrombosis, local inflammation, blood-brain barrier leakage and in some cases extravasation of non-apoptotic monocytes frequently laden with malarial pigment haemozoin (HZ), a lipid-enriched ferriprotoporphyrin IX crystal produced by Plasmodium falciparum after haemoglobin catabolism. In the present work the effects of HZ on IL-1beta regulation in human monocytes were studied. Results showed that phagocytosis of natural HZ promoted praecox mRNA expression and following protein release of IL-1beta. Such an enhancement was dependent on the lipid moiety of HZ, since lipid-free synthetic and delipidized natural HZ did not reproduce these effects. 15(S,R)-hydroxy-6,8,11,13-eicosatetraenoic acid (15-HETE), a potent lipoperoxidation derivative generated by HZ from arachidonic acid through haem-catalysis, mimicked the HZ effects on IL-1beta. Moreover SB203580, a synthetic p38 inhibitor, as well as quercetin, artemisinin and parthenolide, three NF-kappaB inhibitors with antimalarial properties, abrogated either HZ- or 15-HETE-dependent enhancement of IL-1beta. Interestingly, experiments with anti-IL-1beta blocking antibodies or recombinant IL-1beta showed that over-regulated IL-1beta was causally connected to the HZ-dependent enhancement of mRNA expression and protein release of Matrix Metalloproteinase-9 (MMP-9) and Tissue Inhibitor of Metalloproteinase-1 (TIMP-1), two molecules involved in blood-brain barrier damage, activation of cytokine proforms, haemostasis and cell survival. Taken altogether, the present data suggest that in human monocytes the lipid moiety of HZ promotes IL-1beta production trough either p38- or NF-kappaB-dependent mechanisms, and a role for 15-HETE is likely; as a consequence, IL-1beta enhances MMP-9 and TIMP-1, possibly favouring the clinical progress towards CM.
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