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

被引:86
作者
Litjens, NHR
Rademaker, M
Ravensbergen, B
Rea, D
van der Plas, MJA
Thio, B
Walding, A
van Dissel, JT
Nibbering, PH
机构
[1] Leiden Univ, Med Ctr, Dept Infect Dis, NL-2300 RC Leiden, Netherlands
[2] Leiden Univ, Med Ctr, Immunohematol & Bloodbank, NL-2300 RC Leiden, Netherlands
[3] Erasmus MC, Dept Dermatol & Venerol, Rotterdam, Netherlands
[4] AstraZeneca R&D Charnwood, Dept Mol Biol, Loughborough, Leics, England
关键词
dendritic cells; fumarates; lymphocytes; cytokines;
D O I
10.1002/eji.200324174
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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, lipopolysaccharicle-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.
引用
收藏
页码:565 / 575
页数:11
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