Effects of monomethylfumarate on dendritic cell differentiation.
BACKGROUND
Fumaric acid esters (FAE) are effective against psoriasis vulgaris and monomethylfumarate (MMF) is believed to be the most bioactive metabolite of this medication. Earlier we found that the beneficial effects of FAE medication are accompanied by a downregulation of type 1 cytokine production by T-helper (Th) lymphocytes, which are important as they maintain a type 1 cytokine [interferon (IFN)-gamma, interleukin (IL)-2] environment in the skin lesions of psoriasis vulgaris patients and once maximal beneficial effects are obtained type 2 cytokine production is also decreased. In vitro MMF selectively induced type 2 cytokine production by primed Th lymphocytes, whereas type 1 cytokine production by and profileration of T lymphocytes were unaffected.


OBJECTIVE
As dendritic cells (DCs) present in these skin lesions play a key role in the activation of Th lymphocytes, we investigated the effects of MMF on monocyte-derived DC differentiation.


METHODS
Monocytes were differentiated into immature (i) DCs by cytokines with or without MMF. To establish whether these cells were differentiated into iDCs, we analysed the expression of cell surface molecules on these cells and the capacity to capture antigens using flow cytometry. Next, we determined whether these MMF-incubated (MMF-)iDCs could be matured by lipopolysaccharide (LPS) and whether MMF affected this responsiveness as well. For this purpose we measured cytokine production by these LPS-stimulated cells (MMF-DCs) using enzyme-linked immunosorbent assays as well as their ability to activate naive Th lymphocytes.


RESULTS
The presence of MMF during the differentiation of monocytes into iDCs resulted in cells that retained low levels of CD14 and hardly expressed CD1a. Upon maturation, these MMF-iDCs upregulated CD83 and costimulatory molecules and HLA-DR on their surface, indicating that these cells respond to LPS, albeit less than control iDCs. In addition, in response to LPS, MMF-iDCs did not decrease the capacity to capture antigens when compared with control iDCs. MMF-DCs hardly produced IL-12p70 and IL-10 and low levels of tumour necrosis factor (TNF)-alpha, whereas IL-8 produced by MMF-DCs and control DCs did not differ. Moreover, MMF-DCs were less able to induce IFN-gamma production by naive Th lymphocytes compared with control DCs. The production of IL-4 and IL-10 by naive Th lymphocytes cocultured with MMF-DCs did not differ from that by T cells cocultured with control DCs.


CONCLUSIONS
MMF inhibited the monocyte-derived DC differentiation resulting in cells that cannot be appropriately matured to DCs. Consequently, these MMF-DCs are less effective than control DCs in stimulating type 1 cytokine, but not type 2 cytokine production, in Th lymphocytes. This general immunomodulatory effect may in part explain the beneficial effects of FAE therapy in psoriasis.
Litjens
N H R
NH
Department of Infectious Diseases, C5-P, Leiden University Medical Centre, 2300 RC Leiden, The Netherlands.
Rademaker
M
M
Ravensbergen
B
B
Thio
H B
HB
van Dissel
J T
JT
Nibbering
P H
PH
D000954:Antigens, Surface / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D003879:Dermatologic Agents / Q000494:pharmacology*; D004705:Endocytosis / Q000187:drug effects; D005650:Fumarates / Q000494:pharmacology*; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D008298:Maleates / Q000494:pharmacology*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology
D000954:Antigens, Surface; D016207:Cytokines; D003879:Dermatologic Agents; D005650:Fumarates; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008298:Maleates; C073341:citraconic acid