Haemozoin induces early cytokine-mediated lysozyme release from human monocytes through p38 MAPK- and NF-kappaB-dependent mechanisms.
Malarial pigment (natural haemozoin, HZ) is a ferriprotoporphyrin IX crystal produced by Plasmodium parasites after haemoglobin catabolism. HZ-fed human monocytes are functionally compromised, releasing increased amounts of pro-inflammatory molecules, including cytokines, chemokines and cytokine-related proteolytic enzyme Matrix Metalloproteinase-9 (MMP-9), whose role in complicated malaria has been recently suggested. In a previous work HZ was shown to induce through TNFalpha production the release of monocytic lysozyme, an enzyme stored in gelatinase granules with MMP-9. Here, the underlying mechanisms were investigated. Results showed that HZ lipid moiety promoted early but not late lysozyme release. HZ-dependent lysozyme induction was abrogated by anti-TNFalpha/IL-1 beta/MIP-1 alpha blocking antibodies and mimicked by recombinant cytokines. Moreover, HZ early activated either p38 MAPK or NF-kappaB pathways by inducing: p38 MAPK phosphorylation; cytosolic I-kappaB alpha phosphorylation and degradation; NF-kappaB nuclear translocation and DNA-binding. Inhibition of both routes through selected molecules (SB203580, quercetin, artemisinin, parthenolide) prevented HZ-dependent lysozyme release. These data suggest that HZ-triggered overproduction of TNFalpha, IL-1 beta and MIP-1 alpha mediates induction of lysozyme release from human monocytes through activation of p38 MAPK and NF-kappaB pathways, providing new evidence on mechanisms underlying the HZ-enhanced monocyte degranulation in falciparum malaria and the potential role for lysozyme as a new affordable marker in severe malaria.
Dipartimento di Genetica, Biologia e Biochimica, Facoltà di Medicina e Chirurgia, Università degli Studi di Torino, Torino, Italy.
Manuela
M
Polimeni
Elena
E
Valente
Elisabetta
E
Aldieri
Amina
A
Khadjavi
Giuliana
G
Giribaldi
Mauro
M
Prato
D000818:Animals; D054405:Chemokine CCL3 / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology*; D006420:Hemeproteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D008055:Lipids / Q000737:chemistry; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D009113:Muramidase / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000737:chemistry; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
C515429:CCL3 protein, human; D054405:Chemokine CCL3; D016207:Cytokines; D006420:Hemeproteins; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D008055:Lipids; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C020753:hemozoin; D048051:p38 Mitogen-Activated Protein Kinases; D009113:Muramidase