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Mutually enhancing anti‐inflammatory activities of dimethyl fumarate and NF ‐κB inhibitors – implications for dose‐sparing combination therapies
Author(s) -
Hund AnnaCarina,
Lockmann Anike,
Schön Michael P.
Publication year - 2016
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/exd.12892
Subject(s) - dimethyl fumarate , chemistry , pharmacology , psoriasis , cell adhesion molecule , extravasation , nf κb , tumor necrosis factor alpha , in vitro , in vivo , inflammation , bortezomib , cancer research , biochemistry , immunology , medicine , apoptosis , multiple sclerosis , biology , multiple myeloma , microbiology and biotechnology
Fumaric acid esters, dimethyl fumarate (DMF) in particular, have been established for the therapy of psoriasis and, more recently, multiple sclerosis. In the light of therapy‐limiting dose‐dependent side effects, such as gastrointestinal irritation, reducing the effective doses of FAE is a worthwhile goal. In search of strategies to maintain the anti‐inflammatory activity of DMF at reduced concentrations, we found that NF‐κB inhibition augmented key anti‐inflammatory effects of DMF in two complementary experimental settings in vitro . At non‐toxic concentrations, both proteasome inhibition with bortezomib as well as blocking NF‐κB activation through KINK‐1, a small molecule inhibitor of IKKβ‐profoundly enhanced DMF‐dependent inhibition of nuclear NF‐κB translocation in TNFα‐stimulated human endothelial cells. This resulted in significant and selective co‐operative down‐regulation of endothelial adhesion molecules crucial for leucocyte extravasation, namely E‐selectin (CD62E), VCAM‐1 (CD106) and ICAM‐1 (CD54), on both mRNA and protein levels. Functionally, these molecular changes led to synergistically decreased rolling and firm adhesion of human lymphocytes on TNF‐activated endothelial cells, as demonstrated in a dynamic flow chamber system. If our in vitro findings can be translated into clinical settings, it is conceivable that anti‐inflammatory effects of DMF can be achieved with lower doses than currently used, thus potentially reducing unwanted side effects.