Inhibition of Dendritic Cell Differentiation by Fumaric Acid Esters

Zhu, Ke-Cheng; Mrowietz, Ulrich

doi:10.1046/j.1523-1747.2001.01159.x

Cited by 103 publications

(99 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…For example, in lymphocytes, DMF and its hydrolysis product, methylhydrogen fumarate (MHF), modulated cytokine expression toward a Th2 cytokine profile (18,19). Both substances inhibited keratinocyte proliferation (20) and monocyte differentiation into dendritic cells (21).…”

mentioning

confidence: 99%

Dimethylfumarate Inhibits TNF-Induced Nuclear Entry of NF-κB/p65 in Human Endothelial Cells

Loewe

Holnthoner²,

Gröger³

et al. 2002

The Journal of Immunology

184

133

View full text Add to dashboard Cite

Fumaric acid esters, mainly dimethylfumarate (DMF), have been successfully used to treat psoriasis. Based on previous observations that DMF inhibited expression of several TNF-induced genes in endothelial cells, we wished to explore the molecular basis of DMF function in greater detail. In first experiments we analyzed DMF effects on tissue factor expression in human endothelial cells in culture, because tissue factor is expressed by two independent sets of transcription factors, by NF-κB via TNF and by early gene response-1 transcription factor via vascular endothelial growth factor (VEGF). We show that DMF inhibits TNF-induced tissue factor mRNA and protein expression as well as TNF-induced DNA binding of NF-κB proteins, but not VEGF-induced tissue factor protein, mRNA expression, or VEGF-induced early gene response-1 transcription factor/DNA binding. To determine where DMF interferes with the TNF/NF-κB signaling cascade, we next analyzed DMF effects on IκB and on the subcellular distribution of NF-κB. DMF does not inhibit TNF-induced IκBα phosphorylation and IκB degradation; thus, NF-κB is properly released from IκB complexes even in the presence of DMF. Importantly, DMF inhibits the TNF-induced nuclear entry of NF-κB proteins, and this effect appears selective for NF-κB after the release from IκB, because the constitutive shuttling of inactive NF-κB/IκB complexes into and out from the nucleus is not blocked by DMF. Moreover, DMF does not block NF-κB/DNA binding. In conclusion, DMF appears to selectively prevent the nuclear entry of activated NF-κB, and this may be the basis of its beneficial effect in psoriasis.

show abstract

mentioning

confidence: 99%

Dimethylfumarate Inhibits TNF-Induced Nuclear Entry of NF-κB/p65 in Human Endothelial Cells

Loewe

Holnthoner²,

Gröger³

et al. 2002

The Journal of Immunology

184

133

View full text Add to dashboard Cite

show abstract

“…Therefore, in another study we investigated the effects of MMF on the differentiation of monocytes to iDC (our unpublished data). Others already reported that DMF and MMF, but no other fumarates, affected monocyte-derived DC differentiation, as reflected by an inhibition of expression of various costimulatory molecules and a reduced capacity of DC to stimulate T cells [13]. The effects of a 24-h incubation of MMF on cytokine production by DC were dosedependent (maximal inhibitory effect with 100 ?…”

Section: Discussionmentioning

confidence: 92%

“…Since others have reported that high concentrations of DMF may induce apoptosis of cells [13], we first investigated the effect of incubation of monocyte-derived iDC for 24 h with increasing concentrations of MMF on cell viability. FACS analysis revealed that MMF at concentrations up to 100-200 ?…”

Section: Effect Of Mmf On Cytokine Production By DCmentioning

confidence: 99%

“…In this connection, Zhu et al [13] recently showed that both DMF and MMF dose-dependently inhibited the in vitro differentiation of monocytes into immature (i)DC via, at least in the case of DMF, the induction of apoptosis. Recently, we also found that therapeutical concentrations of MMF interfered with the differentiation of monocytes into iDC.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2004

View full text Add to dashboard Cite

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-+ . 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, lipopolysaccharide-stimulated DC (MMF-DC) produced dramatically (p X 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-+ , 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-‹ B activation in DC. Together, beneficial effects of FAE in psoriasis involve modulation of DC polarization by MMF such that these cells down-regulate IFN-+ production by Th cells.

show abstract

“…Auch die deutliche Hemmung der Produktion pro-entzündlicher Zytokine durch DMF wurde beschrieben [305]. Interessanterweise hemmen DMF und MHF die Reifung von dendritischen Zellen, denen bei der Entstehung und Unterhaltung der Immunreaktion bei der Psoriasis vulgaris eine wesentliche Bedeutung zugeschrieben wird [306]. Ältere Arbeiten haben für MHF in vitro an aktivierten T-Zellen die Verschiebung der Sekretion von Th1-artigen Zytokinen zu Th2-artigen beschrieben [307][308][309] [315,319].…”

Section: Zeitraum In Monatenunclassified