Effects of Monomethylfumarate on Human Granulocytes

Nibbering, Peter H.; Thio, Bing; Zomerdijk, Timo P.L.; Bezemer, Anja C.; Beijersbergen, Roderick L.; Furth, R. van

doi:10.1111/1523-1747.ep12358715

Cited by 59 publications

(45 citation statements)

References 22 publications

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“…These effects seem to account, at least in part, for its action as an antipsoriatic agent. These findings, in addition to previously published data, suggest that MMF is exerting inhibitory functions on the three major cell types involved in the pathogenesis of psoriasis (keratinocytes, immune cells, and endothelial cells) (Nibbering et al, 1993;García-Caballero et al, 2011). Together with the clinical data obtained for the antipsoriatic drug Fumaderm (Mrowietz et al, 1998;Rostami Yazdi and Mrowietz, 2008), used in Germany since 1994, these results suggest that MMF may be an ideal therapy for treating moderate to severe psoriasis.…”

Section: Mmf-induced Effects In Keratinocytessupporting

confidence: 74%

“…Data have been published regarding the effects of FAEs (including MMF) on endothelial as well as immune cells; however, little is known about their effects on keratinocytes (Nibbering et al, 1993;Thio et al, 1994;Litjens et al, 2004b;Wallbrecht et al, 2011;Dehmel et al, 2014). Thus, MMF has known effects on immune cells, such as dendritic cells and granulocytes, which could possibly account in part for its antipsoriatic actions (Nibbering et al, 1993;Litjens et al, 2004b).…”

Section: Introductionmentioning

confidence: 99%

“…Thus, MMF has known effects on immune cells, such as dendritic cells and granulocytes, which could possibly account in part for its antipsoriatic actions (Nibbering et al, 1993;Litjens et al, 2004b). In addition, FAEs (including MMF) exhibit inhibitory effects on the proliferation, differentiation, migration, and tube formation of endothelial cells (Arbiser, 2011;García-Caballero et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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The Antipsoriatic Agent Monomethylfumarate Has Antiproliferative, Prodifferentiative, and Anti-Inflammatory Effects on Keratinocytes

Helwa

Patel

Karempelis

et al. 2014

J Pharmacol Exp Ther

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Monomethylfumarate (MMF) is thought to be the bioactive ingredient of the drug Fumaderm (Biogen Idec, Cambridge, MA), licensed in Germany since 1994 for the treatment of moderate-tosevere psoriasis. Psoriasis is a common inflammatory hyperproliferative skin disorder that involves cross-talk between different cell types, including immune cells and keratinocytes. Psoriatic lesions are characterized by hyperproliferation, aberrant differentiation, and inflammation, with the psoriatic cytokine network maintained by communication between immune cells and keratinocytes. Recently, there is increasing evidence regarding the pivotal role of keratinocytes in mediating the disease process, and these cells can be regarded as safe therapeutic targets. From the data available on human subjects treated with Fumaderm, MMF is an effective antipsoriatic agent with known effects on immune cells. However, little is known about its direct effects on keratinocytes. We hypothesized that MMF has direct antiproliferative, prodifferentiative, and anti-inflammatory effects on keratinocytes. Indeed, MMF dose-dependently inhibited [ 3 H]thymidine incorporation into DNA, indicating a direct antiproliferative action on keratinocytes. MMF significantly increased the protein level of keratin 10, the early keratinocyte differentiation marker, and the activity of transglutaminase, a late differentiation marker. These results are consistent with an ability of MMF to promote keratinocyte differentiation and inhibit proliferation, thereby improving psoriatic lesions. In 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced keratinocytes, MMF significantly inhibited the expression of the proinflammatory cytokines, tumor necrosis factor-a (TNFa), interleukin-6, and interleukin-1a as well as the production of TNFa. Our results support the notion that MMF has direct antiproliferative, prodifferentiative, and anti-inflammatory effects on keratinocytes, highlighting its potential use as a multifactorial antipsoriatic agent.

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Section: Mmf-induced Effects In Keratinocytessupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Antipsoriatic Agent Monomethylfumarate Has Antiproliferative, Prodifferentiative, and Anti-Inflammatory Effects on Keratinocytes

Helwa

Patel

Karempelis

et al. 2014

J Pharmacol Exp Ther

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“…Many in vitro studies revealed that FAE, but not fumaric acid (FA), exerted effects on a variety of cell types [10,15]. We therefore compared the effects of DMF, MMF and FA on the LPS/IFN-+ induced cytokine production by DC.…”

Section: Effects Of Dmf and Fumaric Acid On Cytokine Production By DCmentioning

confidence: 98%

“…FAE can be safely applied to patients for a long period because of their well-tolerated and transient side effects [8,9]. This medication consists of dimethylfumarate (DMF) and monoethylfumarate (MEF), while monomethylfumarate (MMF) is its most bioactive metabolite [10]. Although effects of MMF on T cells have been reported [11], the possibility should also be considered that FAE exert effects on cells, such as DC, that regulate the development of the various Th subsets.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2004

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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.

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Clinical Use and Pharmacological Profile of Fumaric Acid Esters

Mrowietz¹

2003

Textbook of Psoriasis

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Effects of Monomethylfumarate on Human Granulocytes

Cited by 59 publications

References 22 publications

The Antipsoriatic Agent Monomethylfumarate Has Antiproliferative, Prodifferentiative, and Anti-Inflammatory Effects on Keratinocytes

The Antipsoriatic Agent Monomethylfumarate Has Antiproliferative, Prodifferentiative, and Anti-Inflammatory Effects on Keratinocytes

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

Clinical Use and Pharmacological Profile of Fumaric Acid Esters

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