Anti-entzündliche Wirkungen in vitro durch Dimethylfumarat und NF-kB-Inhibitoren
Anti-inflammatory effects of dimethyl fumarate and NF-kB-inhibitors in vitro
by Anna-Carina Hund
Date of Examination:2018-09-20
Date of issue:2018-09-17
Advisor:Prof. Dr. Michael P. Schön
Referee:Prof. Dr. Holger Reichardt
Referee:Prof. Dr. Thomas Meyer
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Abstract
English
Fumaric acid esters, dimethyl fumarate (DMF) in particular, have been established for the therapy of psoriasis and became increasingly important for other chronic diseases like multiple sclerosis. Because of a good benefit-to-risk profile, DMF is of great use in the long- term treatment of psoriasis. Despite this, side effects like gastrointestinal complains are limiting the therapy. In the light of dose-dependent side effects we thought of possibilities to maintain the anti-inflammatory activity of DMF at reduced concentrations. Due to the fact that DMF inhibits transcription factor NF-κB and therewith pivotal steps in inflammation, which we confirmed in our experiments, we focused on the augmentation of this inhibition. We showed in two complementary experimental settings in vitro an enhancement of DMF-dependent inhibition of nuclear NF-κB translocation in combination with KINK-1, a small molecule inhibitor of IKKβ, and the proteasome inhibitor Bortezomib. As we detected both on mRNA and protein levels, the combination of DMF and the named NF-κB inhibitors, resulted in significant down-regulation of endothelial adhesion molecules, crucial for leucocyte extravasation, namely E-selectin (CD62E), VCAM-1 (CD106) and ICAM-1 (CD54). Functionally, this decreased rolling and firm adhesion of human lymphocytes on TNF-activated endothelial cells (HUVEC), as demonstrated in a dynamic flow chamber system. In conclusion anti-inflammatory effects of DMF can be achieved with lower doses by combination with NF-κB inhibitors in vitro. If it is possible to translate this results in clinical settings, this would be a possibility to reduce unwanted side effects and improve current therapy.
Keywords: FAE; DMF; Psoriasis; NF-kappaB