Monomethylfumarate affects polarization of monocyte-derived dendritic cells resulting in down-regulated Th1 lymphocyte responses.
Psoriasis vulgaris, a type-1 cytokine-mediated chronic skin disease, can be treated successfully with fumaric acid esters (FAE). Beneficial effects of this medication coincided with decreased production of IFN-gamma. Since dendritic cells (DC) regulate the differentiation of T helper (Th) cells, this study focussed on effects of monomethylfumarate (MMF, bioactive metabolite of FAE) on polarization of monocyte-derived DC. MMF-incubated, lipo-polysaccharide-stimulated DC (MMF-DC) produced dramatically (p<0.05) reduced levels of IL-12p70 and IL-10 (8+/-4% and 20+/-4%, respectively) compared to control DC. MMF-DC were mature. MMF affected polarization of DC irrespective of polarization factor(s) and ligands for the various Toll-like receptors used. Coculture of MMF-DC with naive and primed allogenous Th cells resulted in lymphocytes producing less IFN-gamma, i.e. 59% and 54% of that by the respective Th cells cocultured with control DC. IL-4 production by primed, but not naive Th cells cocultured with MMF-DC was decreased as compared to cocultures with control DC. IL-10 production by naive and primed Th cells cocultured with MMF-DC and control DC did not differ. In addition, MMF inhibited LPS-induced NF-kappaB activation in DC. Together, beneficial effects of FAE in psoriasis involve modulation of DC polarization by MMF such that these cells down-regulate IFN-gamma production by Th cells.
Litjens
Nicolle H R
NH
Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
Rademaker
Mirjam
M
Ravensbergen
Bep
B
Rea
Delphine
D
van der Plas
Mariena J A
MJ
Thio
Bing
B
Walding
Andrew
A
van Dissel
Jaap T
JT
Nibbering
Peter H
PH
D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D016764:Cell Polarity / Q000187:drug effects / Q000276:immunology*; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005650:Fumarates / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D016209:Interleukin-8 / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008298:Maleates / Q000276:immunology / Q000494:pharmacology*; D009000:Monocytes / Q000166:cytology / Q000276:immunology; D021122:Protein Subunits / Q000276:immunology / Q000378:metabolism; D011565:Psoriasis / Q000188:drug therapy / Q000276:immunology*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D015703:Antigens, CD; D005650:Fumarates; D016209:Interleukin-8; D008298:Maleates; D021122:Protein Subunits; D014409:Tumor Necrosis Factor-alpha; C073341:citraconic acid; D016753:Interleukin-10; D018664:Interleukin-12