The antipsoriatic agent monomethylfumarate has antiproliferative, prodifferentiative, and anti-inflammatory effects on keratinocytes

Inas Helwa, Ravi Patel, Peter Karempelis, Ismail Kaddour-Djebbar, Vivek Choudhary, Wendy B Bollag

Research output: Contribution to journalArticle

15 Citations (Scopus)

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 [3H]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-1a 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.

Original languageEnglish (US)
Article numberA20
Pages (from-to)90-97
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume352
Issue number1
DOIs
StatePublished - Jan 1 2015

Fingerprint

Keratinocytes
Anti-Inflammatory Agents
Differentiation Antigens
Psoriasis
Keratin-10
Tumor Necrosis Factor-alpha
citraconic acid
Cytokines
Transglutaminases
Aptitude
Interleukins
Tetradecanoylphorbol Acetate
Thymidine
Germany
Interleukin-6
Communication
Inflammation
Skin
DNA

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

The antipsoriatic agent monomethylfumarate has antiproliferative, prodifferentiative, and anti-inflammatory effects on keratinocytes. / Helwa, Inas; Patel, Ravi; Karempelis, Peter; Kaddour-Djebbar, Ismail; Choudhary, Vivek; Bollag, Wendy B.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 352, No. 1, A20, 01.01.2015, p. 90-97.

Research output: Contribution to journalArticle

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