title: Elastin receptor (spliced galactosidase) occupancy by elastin peptides counteracts proinflammatory cytokine expression in lipopolysaccharide-stimulated human monocytes through NF-kappaB down-regulation.
abstract: In inflammatory diseases, strong release of elastinolytic proteases results in elastin fiber degradation generating elastin peptides (EPs). Chemotactic activity for inflammatory cells was, among wide range of properties, the former identified biological activity exerted by EPs. Recently, we demonstrated the ability of EPs to favor a Th1 cytokine (IL-2, IFN-gamma) cell response in lymphocytes and to regulate IL-1beta expression in melanoma cells. We hypothesized that EPs might also influence inflammatory cell properties by regulating cytokine expression by these cells. Therefore, we investigated the influence of EPs on inflammatory cytokine synthesis by human monocytes. We evidenced that EPs down-regulated both at the mRNA and protein levels the proinflammatory TNF-alpha, IL-1beta, and IL-6 expression in LPS-activated monocytes. Such negative feedback loop could be accounted solely for EP-mediated effects on proinflammatory cytokine production because EPs did not affect anti-inflammatory IL-10 or TGF-beta secretion by LPS-activated monocytes. Furthermore, we demonstrated that EP effect on proinflammatory cytokine expression by LPS-stimulated monocytes could not be due either to a decrease of LPS receptor expression or to an alteration of LPS binding to its receptor. The inhibitory effects of EPs on cytokine expression were found to be mediated by receptor (spliced galactosidase) occupancy, as being suppressed by lactose, and to be associated with the decrease of NF-kappaB-DNA complex formation. As a whole, these results demonstrated that EP/spliced galactosidase interaction on human monocytes down-regulated NF-kappaB-dependent proinflammatory cytokine expression and pointed out the critical role of EPs in the regulation of inflammatory response.
authors.affiliation: Laboratoire d'Immunologie et de Microbiologie, Immuno-Pharmacologie Cellulaire et Moléculaire, EA3796 Unité de Formation et de Recherche de Pharmacie, Reims, France;
authors.forename: Thomas
authors.initials: T
authors.lastname: Baranek
authors.forename: Romain
authors.initials: R
authors.lastname: Debret
authors.forename: Frank
authors.initials: F
authors.lastname: Antonicelli
authors.forename: Bouchaib
authors.initials: B
authors.lastname: Lamkhioued
authors.forename: Azzaq
authors.initials: A
authors.lastname: Belaaouaj
authors.forename: William
authors.initials: W
authors.lastname: Hornebeck
authors.forename: Philippe
authors.initials: P
authors.lastname: Bernard
authors.forename: Moncef
authors.initials: M
authors.lastname: Guenounou
authors.forename: Richard
authors.initials: R
authors.lastname: Le Naour
mesh_terms: D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D004549:Elastin / Q000378:metabolism*; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008545:Melanoma / Q000235:genetics / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D016207:Cytokines; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010446:Peptide Fragments; D020033:Protein Isoforms; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C054901:elastin-binding proteins; D004247:DNA; D004549:Elastin