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The antipsoriatic agent monomethylfumarate has antiproliferative, prodifferentiative, and anti-inflammatory effects
Inas Helwa1, Ravi Patel1, Peter Karempelis1
1Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia (I.H., I.K.-D., V.C., W.B.B.); Department of Oral Biology, College of Dental Medicine, (I.H., W.B.B.), and Departments of Physiology (I.H., R.P., P.K., I.K.-D., V.C., W.B.B.) and Medicine (Dermatology) (V.C., W.B.B.), Medical College of Georgia at Georgia Regents University, Augusta, Georgia.
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-to-severe 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-α (TNFα), interleukin-6, and interleukin-1α as well as the production of TNFα. 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.
Insights
Monomethylfumarate (MMF) directly reduces keratinocyte proliferation and promotes differentiation. This anti-inflammatory agent also inhibits key cytokines, supporting its use for psoriasis treatment.
Area of Science:
- Dermatology
- Immunology
- Cell Biology
Background:
- Psoriasis is a chronic inflammatory skin condition characterized by hyperproliferation and aberrant differentiation of keratinocytes.
- Fumaderm, containing Monomethylfumarate (MMF), is an established treatment for moderate-to-severe psoriasis, primarily known for its effects on immune cells.
- Keratinocytes play a crucial role in psoriasis pathogenesis and are emerging as potential therapeutic targets.
Purpose of the Study:
- To investigate the direct effects of Monomethylfumarate (MMF) on keratinocytes.
- To determine if MMF possesses antiproliferative, prodifferentiative, and anti-inflammatory properties in keratinocytes.
Main Methods:
- Assessed MMF's antiproliferative effect by measuring [(3)H]thymidine incorporation into keratinocyte DNA.
- Evaluated MMF's impact on keratinocyte differentiation by quantifying keratin 10 protein levels and transglutaminase activity.
- Measured MMF's anti-inflammatory effects by analyzing the expression and production of cytokines (TNFα, IL-6, IL-1α) in TPA-induced keratinocytes.
Main Results:
- MMF demonstrated a dose-dependent inhibition of keratinocyte proliferation.
- MMF significantly promoted keratinocyte differentiation, indicated by increased keratin 10 and transglutaminase levels.
- MMF suppressed the expression and production of pro-inflammatory cytokines, including TNFα, IL-6, and IL-1α, in activated keratinocytes.
Conclusions:
- Monomethylfumarate (MMF) exerts direct antiproliferative, prodifferentiative, and anti-inflammatory effects on keratinocytes.
- These findings support MMF's potential as a multifactorial therapeutic agent for psoriasis by targeting keratinocyte dysfunction.
- MMF's direct action on keratinocytes offers a mechanism for its efficacy in managing psoriasis.
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