title: Mutually enhancing anti-inflammatory activities of dimethyl fumarate and NF-κB inhibitors--implications for dose-sparing combination therapies.
abstract: 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.
authors.affiliation: Department of Dermatology, Venereology and Allergology, Georg August University, Göttingen, Germany.
authors.forename: Anna-Carina
authors.initials: AC
authors.lastname: Hund
authors.affiliation: Department of Dermatology, Venereology and Allergology, Georg August University, Göttingen, Germany.
authors.forename: Anike
authors.initials: A
authors.lastname: Lockmann
authors.affiliation: Department of Dermatology, Venereology and Allergology, Georg August University, Göttingen, Germany.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Schön
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000069286:Bortezomib / Q000494:pharmacology; D002448:Cell Adhesion; D000069462:Dimethyl Fumarate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D019040:E-Selectin / Q000096:biosynthesis / Q000235:genetics; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D018056:Hemorheology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D066298:In Vitro Techniques; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D007962:Leukocytes / Q000166:cytology; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010078:Oxazines / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics
chemical_list: C502972:7-(2-(cyclopropylmethoxy)-6-hydroxyphenyl)-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido(2,3-d)(1,3)oxazin-2-one; D000893:Anti-Inflammatory Agents; D019040:E-Selectin; D016328:NF-kappa B; D010078:Oxazines; D011725:Pyridines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex; D000069462:Dimethyl Fumarate
keywords: NF-κB; endothelial cells; fumaric acid esters; inflammation