title: Dimethylfumarate inhibits NF-{kappa}B function at multiple levels to limit airway smooth muscle cell cytokine secretion.
abstract: The antipsoriatic dimethylfumarate (DMF) has been anecdotically reported to reduce asthma symptoms and to improve quality of life of asthma patients. DMF decreases the expression of proinflammatory mediators by inhibiting the transcription factor NF-kappaB and might therefore be of interest for the therapy of inflammatory lung diseases. In this study, we determined the effect of DMF on platelet-derived growth factor (PDGF)-BB- and TNFalpha-induced asthma-relevant cytokines and NF-kappaB activation by primary human asthmatic and nonasthmatic airway smooth muscle cells (ASMC). Confluent nonasthmatic and asthmatic ASMC were incubated with DMF (0.1-100 microM) and/or dexamethasone (0.0001-0.1 microM), NF-kappaB p65 siRNA (100 nM), the NF-kappaB inhibitor helenalin (1 microM) before stimulation with PDGF-BB or TNFalpha (10 ng/ml). Cytokine release was measured by ELISA. NF-kappaB, mitogen and stress-activated kinase (MSK-1), and CREB activation was determined by immunoblotting and EMSA. TNFalpha-induced eotaxin, RANTES, and IL-6 as well as PDGF-BB-induced IL-6 expression was inhibited by DMF and by dexamethasone from asthmatic and nonasthmatic ASMC, but the combination of both drugs showed no glucocorticoid sparing effect in either of the two groups. NF-kappaB p65 siRNA and/or the NF-kappaB inhibitor helenalin reduced PDGF-BB- and TNFalpha-induced cytokine expression, suggesting the involvement of NF-kappaB signaling. DMF inhibited TNFalpha-induced NF-kappaB p65 phosphorylation, NF-kappaB nuclear entry, and NF-kappaB-DNA complex formation, whereas PDGF-BB appeared not to activate NF-kappaB within 60 min. Both stimuli induced the phosphorylation of MSK-1, NF-kappaB p65 at Ser276, and CREB, and all were inhibited by DMF. These data suggest that DMF downregulates cytokine secretion not only by inhibiting NF-kappaB but a wider range of NF-kappaB-linked signaling proteins, which may explain its potential beneficial effect in asthma.
authors.affiliation: Department of Research and Pneumology, University Hospital Basel, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Seidel
authors.forename: I
authors.initials: I
authors.lastname: Merfort
authors.forename: J M
authors.initials: JM
authors.lastname: Hughes
authors.forename: B G G
authors.initials: BG
authors.lastname: Oliver
authors.forename: M
authors.initials: M
authors.lastname: Tamm
authors.forename: M
authors.initials: M
authors.lastname: Roth
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000077214:Becaplermin; D001980:Bronchi / Q000166:cytology* / Q000276:immunology; D002478:Cells, Cultured; D054413:Chemokine CCL11 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D002908:Chronic Disease; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D000069462:Dimethyl Fumarate; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005650:Fumarates / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015850:Interleukin-6 / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D000072000:NF-KappaB Inhibitor alpha; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011014:Pneumonia / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D034741:RNA, Small Interfering; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology; D045789:Sesquiterpenes, Guaiane; D013449:Sulfonamides / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C515456:CCL11 protein, human; C115163:CREB1 protein, human; D054413:Chemokine CCL11; D018946:Chemokine CCL5; D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; D004791:Enzyme Inhibitors; D005650:Fumarates; D005938:Glucocorticoids; D020672:I-kappa B Proteins; C508600:IL6 protein, human; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D007546:Isoquinolines; C000606204:NFKBIA protein, human; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D034741:RNA, Small Interfering; D012717:Sesquiterpenes; D045789:Sesquiterpenes, Guaiane; D013449:Sulfonamides; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D000077214:Becaplermin; C001329:helenalin; D003907:Dexamethasone; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D000069462:Dimethyl Fumarate; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide