Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells

• DOI: 10.1084/jem.20100977
• Publication Date: 2011-10-11T05:28:06Z
• Authors: Kamran Ghoreschi; Jürgen Brück; Christina Kellerer; Caishu Deng; Haiyan Peng; Oliver Rothfuss; Rehana Z. Hussain; Anne R. Gocke; Annedore Respa; Ivana Glocova; Nadejda Valtcheva; Eva Alexander; Susanne Feil; Robert Feil; Klaus Schulze-Ost...; Rudolf A. Rupec; Amy E. Lovett-Racke; Ralf Dringen; Michael K. Racke; Martin Röcken
• Keywords: STAT1; Interleukin-23; Dimethyl fumarate

Fumarates improve multiple sclerosis (MS) and psoriasis, two diseases in which both IL-12 IL-23 promote pathogenic T helper (Th) cell differentiation. However, show opposing responses to most established therapies. First, we humans that fumarate treatment induces IL-4–producing Th2 cells vivo generates type II dendritic (DCs) produce IL-10 instead of IL-23. In mice, fumarates also generate DCs induce vitro protect mice from experimental autoimmune encephalomyelitis. Type result fumarate-induced glutathione (GSH) depletion, followed by increased hemoxygenase-1 (HO-1) expression impaired STAT1 phosphorylation. Induced HO-1 is cleaved, whereupon the N-terminal fragment translocates into nucleus interacts with AP-1 NF-κB sites IL-23p19 promoter. This interaction prevents transcription without affecting IL-12p35, whereas inactivation IL-12p35 IL-23p19. As a consequence, GSH depletion small molecules such as ameliorate inflammatory diseases. therapeutic approach improves Th1- Th17-mediated psoriasis MS interfering production.