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Dimethyl fumarate inhibits dendritic cell maturation via nuclear factor κB (NF-κB) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) and mitogen stress-activated kinase 1 (MSK1) signaling.

Abstract
Dimethyl fumarate (DMF) is an effective novel treatment for multiple sclerosis in clinical trials. A reduction of IFN-γ-producing CD4(+) T cells is observed in DMF-treated patients and may contribute to its clinical efficacy. However, the cellular and molecular mechanisms behind this clinical observation are unclear. In this study, we investigated the effects of DMF on dendritic cell (DC) maturation and subsequent DC-mediated T cell responses. We show that DMF inhibits DC maturation by reducing inflammatory cytokine production (IL-12 and IL-6) and the expression of MHC class II, CD80, and CD86. Importantly, this immature DC phenotype generated fewer activated T cells that were characterized by decreased IFN-γ and IL-17 production. Further molecular studies demonstrated that DMF impaired nuclear factor κB (NF-κB) signaling via reduced p65 nuclear translocalization and phosphorylation. NF-κB signaling was further decreased by DMF-mediated suppression of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and its downstream kinase mitogen stress-activated kinase 1 (MSK1). MSK1 suppression resulted in decreased p65 phosphorylation at serine 276 and reduced histone phosphorylation at serine 10. As a consequence, DMF appears to reduce p65 transcriptional activity both directly and indirectly by promoting a silent chromatin environment. Finally, treatment of DCs with the MSK1 inhibitor H89 partially mimicked the effects of DMF on the DC signaling pathway and impaired DC maturation. Taken together, these studies indicate that by suppression of both NF-κB and ERK1/2-MSK1 signaling, DMF inhibits maturation of DCs and subsequently Th1 and Th17 cell differentiation.
AuthorsHaiyan Peng, Mireia Guerau-de-Arellano, Veela B Mehta, Yuhong Yang, David J Huss, Tracey L Papenfuss, Amy E Lovett-Racke, Michael K Racke
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 287 Issue 33 Pg. 28017-26 (Aug 10 2012) ISSN: 1083-351X [Electronic] United States
PMID22733812 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • B7-1 Antigen
  • B7-2 Antigen
  • Cd86 protein, mouse
  • Fumarates
  • Histocompatibility Antigens Class II
  • Immunosuppressive Agents
  • Interleukin-6
  • Rela protein, mouse
  • Transcription Factor RelA
  • Interleukin-12
  • Ribosomal Protein S6 Kinases, 90-kDa
  • mitogen and stress-activated protein kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Dimethyl Fumarate
Topics
  • Animals
  • B7-1 Antigen (biosynthesis, immunology)
  • B7-2 Antigen (biosynthesis, immunology)
  • Cell Differentiation (drug effects, immunology)
  • Cells, Cultured
  • Dendritic Cells (cytology, immunology, metabolism)
  • Dimethyl Fumarate
  • Fumarates (pharmacology)
  • Histocompatibility Antigens Class II (biosynthesis, immunology)
  • Immunosuppressive Agents (pharmacology)
  • Interleukin-12 (immunology, metabolism)
  • Interleukin-6 (immunology, metabolism)
  • MAP Kinase Signaling System (drug effects, immunology)
  • Mice
  • Mitogen-Activated Protein Kinase 3 (immunology, metabolism)
  • Phosphorylation (drug effects, immunology)
  • Ribosomal Protein S6 Kinases, 90-kDa (immunology, metabolism)
  • Th1 Cells (cytology, immunology, metabolism)
  • Th17 Cells (cytology, immunology, metabolism)
  • Transcription Factor RelA (immunology, metabolism)

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