title: Carbon monoxide inhibits TLR-induced dendritic cell immunogenicity.
abstract: Heme oxygenase-1 (HO-1) exerts its functions via the catabolism of heme into carbon monoxide (CO), Fe(2+), and biliverdin, as well as by depletion of free heme. We have recently described that overexpression of HO-1 is associated with the tolerogenic capacity to dendritic cells (DCs) stimulated by LPS. In this study, we demonstrate that treatment of human monocyte-derived DCs with CO blocks TLR3 and 4-induced phenotypic maturation, secretion of proinflammatory cytokines, and alloreactive T cell proliferation, while preserving IL-10 production. Treatment of DCs with biliverdin, bilirubin, and deferoxamine or replenishing intracellular heme stores had no effect on DC maturation. HO-1 and CO inhibited LPS-induced activation of the IFN regulatory factor 3 pathway and their effects were independent of p38, ERK, and JNK MAPK. HO-1 and CO treatment also inhibited mouse DC maturation in vitro and mouse DC immunogenic properties in vivo, as shown by adoptive cell transfer in a transgenic model of induced diabetes. Thus, for the first time, our data show that CO treatment inhibits DC immunogenicity induced by TLR ligands and that blockade of IFN regulatory factor 3 is associated with this effect.
authors.affiliation: Institut National de Santé et de Recherche Médicale, Unité 643, Nantes, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Rémy
authors.forename: Philippe
authors.initials: P
authors.lastname: Blancou
authors.forename: Laurent
authors.initials: L
authors.lastname: Tesson
authors.forename: Virginie
authors.initials: V
authors.lastname: Tardif
authors.forename: Régis
authors.initials: R
authors.lastname: Brion
authors.forename: Pierre Joseph
authors.initials: PJ
authors.lastname: Royer
authors.forename: Roberto
authors.initials: R
authors.lastname: Motterlini
authors.forename: Roberta
authors.initials: R
authors.lastname: Foresti
authors.forename: Marion
authors.initials: M
authors.lastname: Painchaut
authors.forename: Sylvie
authors.initials: S
authors.lastname: Pogu
authors.forename: Marc
authors.initials: M
authors.lastname: Gregoire
authors.forename: Jean Marie
authors.initials: JM
authors.lastname: Bach
authors.forename: Ignacio
authors.initials: I
authors.lastname: Anegon
authors.forename: Christine
authors.initials: C
authors.lastname: Chauveau
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002248:Carbon Monoxide / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005434:Flow Cytometry; D051547:Heme Oxygenase-1 / Q000276:immunology; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000276:immunology* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology* / Q000378:metabolism
chemical_list: C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors; D002248:Carbon Monoxide; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1