Role of 15-hydroxyeicosatetraenoic acid in hemozoin-induced lysozyme release from human adherent monocytes.
Natural hemozoin (nHZ), a lipid-bound ferriprotoporphyrin IX crystal produced by Plasmodium parasites after hemoglobin catabolism, seriously compromises the functions of human monocytes, and 15-hydroxyeicosatetraenoic acid (15-HETE) and 4-hydroxynonenal (4-HNE), two nHZ lipoperoxidation products, have been related to such a functional impairment. nHZ was recently shown to promote inflammation-mediated lysozyme release from human monocytes through p38 mitogen-activated protein kinase- (MAPK)- and nuclear factor (NF)-κB-dependent mechanisms. This study aimed at identifying the molecule of nHZ lipid moiety that was responsible for these effects. Results showed that 15-HETE mimicked nHZ effects on lysozyme release, whereas 4-HNE did not. 15-HETE-enhanced lysozyme release was abrogated by anti-TNF-α and anti-IL-1β-blocking antibodies and mimicked by recombinant cytokines; on the contrary, MIP-1α/CCL3 was not involved as a soluble mediator of 15-HETE effects. Moreover, 15-HETE early activated p38 MAPK and NF-κB pathways by inducing p38 MAPK phosphorylation; cytosolic I-κBα phosphorylation and degradation; NF-κB nuclear translocation and DNA-binding. Inhibition of both routes through chemical inhibitors (SB203580, quercetin, artemisinin, and parthenolide) prevented 15-HETE-dependent lysozyme release. Collectively, these data suggest that 15-HETE plays a major role in nHZ-enhanced monocyte degranulation.
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
D000447:Aldehydes / Q000494:pharmacology; D037621:Artemisinins / Q000494:pharmacology; D002478:Cells, Cultured; D054405:Chemokine CCL3 / Q000378:metabolism; D005434:Flow Cytometry; D006420:Hemeproteins / Q000494:pharmacology*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism*; D009113:Muramidase / Q000187:drug effects* / Q000378:metabolism*; D010587:Phagocytosis / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D011794:Quercetin / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D012717:Sesquiterpenes / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000447:Aldehydes; D037621:Artemisinins; D054405:Chemokine CCL3; D006420:Hemeproteins; D006893:Hydroxyeicosatetraenoic Acids; D007093:Imidazoles; D053583:Interleukin-1beta; D011725:Pyridines; D012717:Sesquiterpenes; D014409:Tumor Necrosis Factor-alpha; C002669:parthenolide; C020753:hemozoin; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D011794:Quercetin; C031327:artemisinin; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D009113:Muramidase; C027576:4-hydroxy-2-nonenal; C093642:SB 203580