title: Inhibition of dendritic cell differentiation by fumaric acid esters.
abstract: Fumaric acid esters have proved to be effective for the systemic treatment of severe psoriasis vulgaris. These compounds have been shown to induce a Th2-like cytokine secretion pattern in T cells and to reduce keratinocyte proliferation in vitro. Dendritic cells seem to be of major importance as regulatory cells driving the psoriatic tissue reaction. Monocytes or CD34-positive myeloid progenitor cells are precursors of dendritic cells that can be generated in vitro by culture with granulocyte-macrophage colony-stimulating factor and interleukin-4. Using this model the effect of fumaric acid esters on granulocyte-macrophage colony-stimulating factor/interleukin-4-induced differentiation of monocyte-derived dendritic cells was investigated. The results of this study show that dimethylfumarate as well as methylhydrogenfumarate-calcium-salt (0.01-100 microg per ml) concentration-dependently inhibit monocyte-derived dendritic cell differentiation. This was reflected by an inhibition of CD1a, CD40, CD80, CD86, and HLA-DR expression as well as by a reduced capacity of dimethylfumarate-treated monocyte-derived dendritic cells to stimulate lymphocytes in the allogeneic mixed lymphocyte reaction. Other fumaric acid esters showed no effect on monocyte-derived dendritic cell-differentiation. At higher concentrations (30-100 microg per ml) dimethylfumarate, but not methylhydrogenfumarate calcium-salt induced apoptosis in monocyte-derived dendritic cells as measured by expression of Apo 2.7 and DNA fragmentation (TUNEL assay). These data point to a high susceptibility of the monocyte/dendritic cell system to dimethylfumarate and its main metabolite methylhydrogenfumarate. Other fumaric acid esters investigated were without effect. As the effects of fumarates on monocyte-derived dendritic cells observed occur at concentrations 20-fold lower compared with lymphocytes, our data seem to be of relevance in explaining the possible mode of action of these compounds in psoriasis.
authors.affiliation: Department of Dermatology, University of Kiel, Schittenhelmstr. 7, 24105 Kiel, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Zhu
authors.forename: U
authors.initials: U
authors.lastname: Mrowietz
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000917:Antibody Formation / Q000187:drug effects; D017951:Antigen Presentation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival; D003713:Dendritic Cells / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D005650:Fumarates / Q000494:pharmacology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D009000:Monocytes / Q000166:cytology; D011565:Psoriasis / Q000188:drug therapy / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D005650:Fumarates