pro-differentiative and anti-inflammatory effects on keratinocytes

Monomethylfumarate (MMF) is thought to be the bioactive ingredient of the drug Fumaderm, 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 anti-psoriatic agent with known effects on immune cells. However, little is known about its direct effects on keratinocytes. We hypothesized that MMF has direct anti-proliferative, pro-differentiative and anti-inflammatory effects on keratinocytes. Indeed, MMF dose-dependently inhibited [H]thymidine incorporation into DNA, indicating a direct anti-proliferative action on keratinocytes. MMF significantly increased the protein level of the early keratinocyte differentiation marker, keratin 10 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 pro-inflammatory cytokines, tumor necrosis factoralpha (TNFα), interleukin-6 and interleukin-1α as well as the production of TNFα. Our results support the notion that MMF has direct anti-proliferative, pro-differentiative and antiinflammatory effects on keratinocytes, highlighting its potential use as a multifactorial antipsoriatic agent. This article has not been copyedited and formatted. The final version may differ from this version. JPET Fast Forward. Published on October 20, 2014 as DOI: 10.1124/jpet.114.218818 at A PE T Jornals on O cber 9, 2017 jpet.asjournals.org D ow nladed from