Monomethylfumarate affects polarization of monocyte-derived dendritic cells resulting in down-regulated Th1 lymphocyte responses

TY - JOUR

T1 - Monomethylfumarate affects polarization of monocyte-derived dendritic cells resulting in down-regulated Th1 lymphocyte responses

AU - Litjens, Nicolle H R

AU - Rademaker, Mirjam

AU - Ravensbergen, Bep

AU - Rea, Delphine

AU - van der Plas, Mariena J A

AU - Thio, Bing

AU - Walding, Andrew

AU - van Dissel, Jaap T

AU - Nibbering, Peter H

PY - 2004/2

Y1 - 2004/2

N2 - 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.

AB - 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.

KW - Antigens, CD

KW - Cell Differentiation

KW - Cell Polarity

KW - Coculture Techniques

KW - Dendritic Cells

KW - Down-Regulation

KW - Enzyme-Linked Immunosorbent Assay

KW - Flow Cytometry

KW - Fumarates

KW - Humans

KW - Interleukin-10

KW - Interleukin-12

KW - Interleukin-8

KW - Lymphocyte Activation

KW - Maleates

KW - Monocytes

KW - Protein Subunits

KW - Psoriasis

KW - Th1 Cells

KW - Tumor Necrosis Factor-alpha

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1002/eji.200324174

DO - 10.1002/eji.200324174

M3 - Journal article

C2 - 14768062

SN - 0014-2980

VL - 34

SP - 565

EP - 575

JO - European Journal of Immunology

JF - European Journal of Immunology

IS - 2

ER -