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: 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-Osthoff, Rudolf A Rupec, Amy E Lovett-Racke, Ralf Dringen, Michael K Racke, Martin Röcken
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 208 Issue 11 Pg. 2291-303 (Oct 24 2011) ISSN: 1540-9538 [Electronic] United States
• PMID: 21987655 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Fumarates
• Interleukin-23
• Reactive Oxygen Species
• Rela protein, mouse
• Transcription Factor RelA
• Interleukin-12
• Heme Oxygenase-1

Topics

• Animals
• Cell Differentiation (immunology)
• Dendritic Cells (cytology, drug effects, immunology)
• Encephalomyelitis, Autoimmune, Experimental (immunology)
• Female
• Fumarates (immunology, therapeutic use)
• Heme Oxygenase-1 (metabolism)
• Humans
• Interleukin-12 (immunology)
• Interleukin-23 (immunology)
• Macrophages (immunology)
• Mice
• Multiple Sclerosis (drug therapy, immunology)
• NIH 3T3 Cells
• Promoter Regions, Genetic
• Psoriasis (drug therapy, immunology)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (immunology)
• T-Lymphocytes (cytology, immunology)
• Transcription Factor RelA (metabolism)