title: Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells.
abstract: Fumarates improve multiple sclerosis (MS) and psoriasis, two diseases in which both IL-12 and IL-23 promote pathogenic T helper (Th) cell differentiation. However, both diseases show opposing responses to most established therapies. First, we show in humans that fumarate treatment induces IL-4-producing Th2 cells in vivo and generates type II dendritic cells (DCs) that produce IL-10 instead of IL-12 and IL-23. In mice, fumarates also generate type II DCs that induce IL-4-producing Th2 cells in vitro and in vivo and protect mice from experimental autoimmune encephalomyelitis. Type II DCs result from fumarate-induced glutathione (GSH) depletion, followed by increased hemoxygenase-1 (HO-1) expression and impaired STAT1 phosphorylation. Induced HO-1 is cleaved, whereupon the N-terminal fragment of HO-1 translocates into the nucleus and interacts with AP-1 and NF-κB sites of the IL-23p19 promoter. This interaction prevents IL-23p19 transcription without affecting IL-12p35, whereas STAT1 inactivation prevents IL-12p35 transcription without affecting IL-23p19. As a consequence, GSH depletion by small molecules such as fumarates induces type II DCs in mice and in humans that ameliorate inflammatory autoimmune diseases. This therapeutic approach improves Th1- and Th17-mediated autoimmune diseases such as psoriasis and MS by interfering with IL-12 and IL-23 production.
authors: Department of Dermatology, University Medical Center and 2 Interfaculty Institute for Biochemistry, Eberhard Karls University Tübingen, Tübingen, Germany.
authors: Kamran
authors: K
authors: Ghoreschi
authors: Jürgen
authors: J
authors: Brück
authors: Christina
authors: C
authors: Kellerer
authors: Caishu
authors: C
authors: Deng
authors: Haiyan
authors: H
authors: Peng
authors: Oliver
authors: O
authors: Rothfuss
authors: Rehana Z
authors: RZ
authors: Hussain
authors: Anne R
authors: AR
authors: Gocke
authors: Annedore
authors: A
authors: Respa
authors: Ivana
authors: I
authors: Glocova
authors: Nadejda
authors: N
authors: Valtcheva
authors: Eva
authors: E
authors: Alexander
authors: Susanne
authors: S
authors: Feil
authors: Robert
authors: R
authors: Feil
authors: Klaus
authors: K
authors: Schulze-Osthoff
authors: Rudolf A
authors: RA
authors: Rupec
authors: Amy E
authors: AE
authors: Lovett-Racke
authors: Ralf
authors: R
authors: Dringen
authors: Michael K
authors: MK
authors: Racke
authors: Martin
authors: M
authors: Röcken
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D005260:Female; D005650:Fumarates / Q000276:immunology* / Q000627:therapeutic use*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology; D053759:Interleukin-23 / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology*; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic; D011565:Psoriasis / Q000188:drug therapy* / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D005650:Fumarates; D053759:Interleukin-23; D017382:Reactive Oxygen Species; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D018664:Interleukin-12; D051547:Heme Oxygenase-1