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* Institut National de la Santé et de la Recherche Médicale, Unité 643, Nantes, France;
Centre Hospitalier Universitaire Nantes, Institut de Transplantation et de Recherche en Transplantation, Institut de Transplantation et de Recherche en Transplantation-Urologie-Néphrologie, Nantes, France;
Université de Nantes, Faculté de Médecine, Nantes, France;
Institut National de la Recherche Argonomique, Ecole Nationale Vétérinaire, Université de Nantes, France;
¶ Institut National de la Santé et de la Recherche Médicale, Unité 601, Nantes, France; and
|| Department of Surgical Research, Vascular Biology Unit, Northwick Park Institute for Medical Research. Harrow, United Kingdom
Heme oxygenase-1 (HO-1) exerts its functions via the catabolism of heme into carbon monoxide (CO), Fe2+, 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This project was funded by the Fondation Progreffe, Roche Organ Transplantation Research Foundation Grant 936864657 (to I.A.), and the ImmunoIntervention et Biothérapies network funded by the Région Pays de la Loire through the Core Facility Research and Development for Clinical Transfer.
2 S.R. and P.B. contributed equally to this work.
3 I.A. and C.C. share senior authorship.
4 Address correspondence and reprint requests to Dr. Ignacio Anegon and Dr. Christine Chauveau, Institut National de la Santé et de la Recherche Médicale, Unité 643, Centre Hospitalier Régional Universitaire, Nantes, 30 boulevard Jean Monnet, 44093 Nantes, France. E-mail addresses: ianegon{at}nantes.inserm.fr and chauveau{at}nantes.inserm.fr
5 Abbreviations used in this paper: CO, carbon monoxide; DC, dendritic cell; iDC, immature DC; HO-1, heme oxygenase 1; IRF-3, IFN regulatory factor 3; HA, hemagglutinin; CoPP, cobalt protoporphyrin; MnPP, manganese protoporphyrin; CORM2, tricarbonyldichlororuthenium(II) dimer; iCORM, inactive form of CORM2; BV, biliverdin; BL, bilirubin; DFO, deferoxamine; poly(I:C), polyinosinic:polycytidylic acid; [3H]Td, [3H]thymidine; TRIF, TIR domain adaptor-inducing IFN.
6 The online version of this article contains supplemental material.
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