title: Hydroxytyrosol suppresses MMP-9 and COX-2 activity and expression in activated human monocytes via PKCα and PKCβ1 inhibition.
abstract: OBJECTIVE
  Hydroxytyrosol (HT), the major olive oil antioxidant polyphenol in cardioprotective Mediterranean diets, is endowed with anti-inflammatory and anti-atherosclerotic activity. The production of cyclooxygenase (COX)-2-dependent inflammatory eicosanoids and the functionally linked release of matrix metalloproteinase (MMP)-9 by macrophages likely contribute to plaque instability leading to acute coronary events. Objective of the study was to examine the HT effects on inflammatory markers in human activated monocytes, including MMP-9 and COX-2 activity and expression and explore HT underlying mechanisms.
  
  
  RESULTS
  Human peripheral blood mononuclear cells (PBMC) and U937 monocytes were treated with 1-10 μmol/L HT before activation with phorbol myristate acetate (PMA). HT blunted monocyte matrix invasive potential and reduced MMP-9 release and expression at zymography, ELISA and RT-PCR, with an IC50 = 10 μmol/L ( P< 0.05), without affecting tissue inhibitor of metalloproteinase (TIMP)-1. Moreover, HT inhibited prostaglandin (PG)E2 production and COX-2 expression, without affecting COX-1. These effects were mediated by inhibition of transcription factor nuclear factor (NF)-κB and protein kinase C (PKC)α and PKCβ1 activation.
  
  
  CONCLUSIONS
  HT, at nutritionally relevant concentrations, reduces MMP-9 and COX-2 induction in activated human monocytes via PKCα and PKCβ1 inhibition, thus featuring novel anti-inflammatory properties. Overall, such results contribute to explaining the vascular protective effects by olive oil polyphenols in Mediterranean diets.
authors.affiliation: National Research Council (CNR), Institute of Clinical Physiology (IFC), Lecce, Italy.
authors.forename: Egeria
authors.initials: E
authors.lastname: Scoditti
authors.affiliation: National Research Council (CNR), Institute of Clinical Physiology (IFC), Lecce, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Nestola
authors.affiliation: National Research Council (CNR), Institute of Clinical Physiology (IFC), Lecce, Italy.
authors.forename: Marika
authors.initials: M
authors.lastname: Massaro
authors.affiliation: National Research Council (CNR), Institute of Clinical Physiology (IFC), Lecce, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Calabriso
authors.affiliation: Department of Biological and Environmental Science and Technologies, University of Salento, Lecce, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Storelli
authors.affiliation: "G. Monasterio" Foundation for Clinical Research, Pisa, Italy; "G. d'Annunzio" University and Center of Excellence on Aging, Chieti, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Caterina
authors.affiliation: National Research Council (CNR), Institute of Clinical Physiology (IFC), Lecce, Italy. Electronic address: maria.carluccio@ifc.cnr.it.
authors.forename: Maria Annunziata
authors.initials: MA
authors.lastname: Carluccio
mesh_terms: D051546:Cyclooxygenase 2 / Q000378:metabolism*; D038441:Diet, Mediterranean; D015536:Down-Regulation; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D007249:Inflammation; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008264:Macrophages / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000201:enzymology*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D000069463:Olive Oil; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000737:chemistry; D010703:Phorbol Esters; D010938:Plant Oils / Q000737:chemistry; D059808:Polyphenols / Q000737:chemistry; D064546:Protein Kinase C beta / Q000378:metabolism*; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D015398:Signal Transduction; D020298:U937 Cells
chemical_list: D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D000069463:Olive Oil; D010703:Phorbol Esters; D010938:Plant Oils; D059808:Polyphenols; C005975:3,4-dihydroxyphenylethanol; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C496628:PRKCA protein, human; C579054:PRKCB protein, human; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D010626:Phenylethyl Alcohol
keywords: Cyclooxygenase-2; Hydroxytyrosol; Inflammation; Matrix metalloproteinase-9; Nuclear factor-κB; Oxidative stress; Protein kinase C