title: Involvement of p38 MAPK in haemozoin-dependent MMP-9 enhancement in human monocytes.
abstract: The lipid moiety of natural haemozoin (nHZ, malarial pigment) was previously shown to enhance expression and release of human monocyte matrix metalloproteinase-9 (MMP-9), and a major role for 15-(S,R)-hydroxy-6,8,11,13-eicosatetraenoic acid (15-HETE), a nHZ lipoperoxidation product, was proposed. Here, the underlying mechanisms were investigated, focusing on the involvement of mitogen-activated protein kinases (MAPKs). Results showed that nHZ promoted either early or late p38 MAPK phosphorylation; however, nHZ did not modify basal phosphorylation/expression ratios of extracellular signal-regulated kinase-1/2 and c-jun N-terminal kinase-1/2. 15-HETE mimicked nHZ effects on p38 MAPK, whereas lipid-free synthetic (s)HZ and delipidized (d)HZ did not. Consistently, both nHZ and 15-HETE also promoted phosphorylation of MAPK-activated protein kinase-2, a known p38 MAPK substrate; such an effect was abolished by SB203580, a synthetic p38 MAPK inhibitor. SB203580 also abrogated nHZ-dependent and 15-HETE-dependent enhancement of MMP-9 mRNA and protein (latent and activated forms) levels in cell lysates and supernatants. Collectively, these data suggest that in human monocytes, nHZ and 15-HETE upregulate MMP-9 expression and secretion through activation of p38 MAPK pathway. The present work provides new evidence on mechanisms underlying MMP-9 deregulation in malaria, which might be helpful to design new specific drugs for adjuvant therapy in complicated malaria.
authors.affiliation: Dipartimento di Genetica, Biologia e Biochimica, Università di Torino, Turin, Italy.
authors.forename: Amina
authors.initials: A
authors.lastname: Khadjavi
authors.forename: Elena
authors.initials: E
authors.lastname: Valente
authors.forename: Giuliana
authors.initials: G
authors.lastname: Giribaldi
authors.forename: Mauro
authors.initials: M
authors.lastname: Prato
mesh_terms: D002448:Cell Adhesion; D005260:Female; D006420:Hemeproteins / Q000378:metabolism*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D010587:Phagocytosis; D010766:Phosphorylation; D010860:Pigments, Biological / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000737:chemistry; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D006420:Hemeproteins; D006893:Hydroxyeicosatetraenoic Acids; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D020780:Matrix Metalloproteinase 9; D010860:Pigments, Biological; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C020753:hemozoin; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; C579270:MMP9 protein, human; C093642:SB 203580
keywords: 15-(S,R)-hydroxy-6,8,11,13-eicosatetraenoic acid (15-HETE); P. falciparum malaria; haemozoin (HZ); human monocyte; matrix metalloproteinase-9 (MMP-9); p38 mitogen-activated protein kinase (P38 MAPK)