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

Abstract

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.

Dimethyl fumarate–induced lymphopenia in MS due to differential T-cell subset apoptosis

“…Memory and naive T cells are known to proliferate at different rates, with a greater steady-state proliferation rate of memory T cells, 32 and antiproliferative effects of FAEs (including both DMF and MMF) have been reported. 5,33 …”

Efficacy, effectiveness and safety of fumaric acid esters in the treatment of psoriasis: a systematic review of randomized and observational studies

“…DMF is considered the most active FAE and thought to improve psoriasis via various immunomodulating, antiproliferative and antiangiogenic effects. [21][22][23][24] Importantly, DMF is a prodrug. The metabolites monomethylfumarate (MMF) and S-(1,2-dimethoxycarbonylethyl)glutathione are the in vivo moieties; MMF is the bioactive metabolite.…”

“…The mechanisms of action of FAEs are not completely understood. DMF is considered the most active FAE and thought to improve psoriasis via various immunomodulating, antiproliferative and antiangiogenic effects . Importantly, DMF is a prodrug.…”

Ameliorative effects of gallic acid on cardio-renal complexity induced by isoproterenol

“…Agents that are able to inhibit keratinocyte proliferation/differentiation and induce keratinocyte apoptosis therefore possess good potential for being employed as effective agents in psoriasis treatment. Most of the pharmacologically available anti-psoriatic treatments deliver their therapeutic effects mainly by targeting the hyper-proliferative activity of keratinocytes [9,11,[30][31] . Thus, an effective and reliable anti-psoriatic medication could be thought of as one that ideally displays low toxicity and maintains epidermal homeostasis by inhibiting keratinocyte hyperproliferation and/or abnormal differentiation with skin rejuvenating effects.…”

“…While there is no complete cure for psoriasis, given the intrinsic hyper proliferative nature of epidermal keratinocyte cells during psoriatic conditions, antipsoriatic therapies aimed at regulation of keratinocytic proliferation and differentiation are highly reliable in treating psoriatic skin, since restoration of homeostatic regulation of keratinocyte proliferation, growth and differentiation is a critical event necessary for normalization and recovery of psoriatic skin [9][10][11][12] . Several of the available and established anti-psoriatic treatments are topical therapies such as those involving vitamin-A and D3 analogs, tazarotene dithranol, monomethylfumarate, fumaderm, artemether hydroxyl urea, methotraxate etc., all of which are based on the anti-proliferative and apoptosis inducing properties of the synthetic/semi-synthetic drugs [13][14][15][16] .…”