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In this study, we determined the effect of DMF on platelet-derived growth factor (PDGF)-BB- and TNF\u03b1-induced asthma-relevant cytokines and NF-\u03baB activation by primary human asthmatic and nonasthmatic airway smooth muscle cells (ASMC). Confluent nonasthmatic and asthmatic ASMC were incubated with DMF (0.1\u2013100 \u03bcM) and\/or dexamethasone (0.0001\u20130.1 \u03bcM), NF-\u03baB p65 siRNA (100 nM), the NF-\u03baB inhibitor helenalin (1 \u03bcM) before stimulation with PDGF-BB or TNF\u03b1 (10 ng\/ml). Cytokine release was measured by ELISA. NF-\u03baB, mitogen and stress-activated kinase (MSK-1), and CREB activation was determined by immunoblotting and EMSA. TNF\u03b1-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-\u03baB p65 siRNA and\/or the NF-\u03baB inhibitor helenalin reduced PDGF-BB- and TNF\u03b1-induced cytokine expression, suggesting the involvement of NF-\u03baB signaling. DMF inhibited TNF\u03b1-induced NF-\u03baB p65 phosphorylation, NF-\u03baB nuclear entry, and NF-\u03baB-DNA complex formation, whereas PDGF-BB appeared not to activate NF-\u03baB within 60 min. Both stimuli induced the phosphorylation of MSK-1, NF-\u03baB p65 at Ser276, and CREB, and all were inhibited by DMF. These data suggest that DMF downregulates cytokine secretion not only by inhibiting NF-\u03baB but a wider range of NF-\u03baB-linked signaling proteins, which may explain its potential beneficial effect in asthma. <\/jats:p>","DOI":"10.1152\/ajplung.90624.2008","type":"journal-article","created":{"date-parts":[[2009,5,23]],"date-time":"2009-05-23T01:12:27Z","timestamp":1243041147000},"page":"L326-L339","source":"Crossref","is-referenced-by-count":77,"title":["Dimethylfumarate inhibits NF-\u03baB function at multiple levels to limit airway smooth muscle cell cytokine secretion"],"prefix":"10.1152","volume":"297","author":[{"given":"P.","family":"Seidel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I.","family":"Merfort","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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