title: Transplant tolerance is associated with reduced expression of cystathionine-γ-lyase that controls IL-12 production by dendritic cells and TH-1 immune responses.
abstract: Antigen-activated T lymphocytes undergo an immune or tolerogeneic response in part according to the activation status of their antigen-presenting cells. However, factors controlling the activation of antigen-presenting cells are not fully understood. In this study, we demonstrate that immune tolerance after organ allotransplantation in the rat is associated with a repressed intragraft expression of several enzymes of the trans-sulfuration pathway, including cystathionine γ-lyase (CSE). The pharmacologic blockade of CSE with propargylglycine delayed heart allograft rejection and abrogated type IV hypersensitivity but did not modify antibody responses, and was associated with a selective inhibition of the TH-1 type factors T-bet, IL-12, and IFN-γ. IL-12 repression could also be induced by propargylglycine in vitro in monocytes and dendritic cells (DCs), a phenomenon not mediated by changes to nuclear factor-κ B or hydrogen sulfide but that occurred together with a modulation of intracellular cysteine content. Intracellular cysteine levels were predominantly controlled in DCs by CSE activity, together with extracellular import via the X(c)(-) transporter. Our results indicate that CSE plays a critical role in regulating IL-12 in monocytes and DCs and is down-modulated in transplant tolerance, presumably participating in the maintenance of the tolerant state.
authors.affiliation: Inserm, Unité Mixte de Recherche-S1064, Institut de Transplantation Urologie Nephrologie, Nantes, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Vuillefroy de Silly
authors.forename: Flora
authors.initials: F
authors.lastname: Coulon
authors.forename: Nicolas
authors.initials: N
authors.lastname: Poirier
authors.forename: Vojislav
authors.initials: V
authors.lastname: Jovanovic
authors.forename: Sophie
authors.initials: S
authors.lastname: Brouard
authors.forename: Véronique
authors.initials: V
authors.lastname: Ferchaud-Roucher
authors.forename: Gilles
authors.initials: G
authors.lastname: Blancho
authors.forename: Bernard
authors.initials: B
authors.lastname: Vanhove
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D003540:Cystathionine / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006084:Graft Rejection / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism*; D016030:Kidney Transplantation / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011917:Rats, Inbred Lew; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018417:Th1 Cells / Q000276:immunology*; D023001:Transplantation Tolerance / Q000276:immunology*
chemical_list: D015415:Biomarkers; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018664:Interleukin-12; D003540:Cystathionine; D007371:Interferon-gamma; D003542:Cystathionine gamma-Lyase