Dimethylfumarate inhibits NF-κB function at multiple levels to limit airway smooth muscle cell cytokine secretion

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Journal Article
American Journal of Physiology - Lung Cellular and Molecular Physiology, 2009, 297 (2)
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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-κB 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 TNFα-induced asthma-relevant cytokines and NF-κB activation by primary human asthmatic and nonasthmatic airway smooth muscle cells (ASMC). Confluent nonasthmatic and asthmatic ASMC were incubated with DMF (0.1-100 μM) and/or dexamethasone (0.0001-0.1 μM), NF-κB p65 siRNA (100 nM), the NF-κB inhibitor helenalin (1 μM) before stimulation with PDGF-BB or TNFα (10 ng/ml). Cytokine release was measured by ELISA. NF-κB, mitogen and stress-activated kinase (MSK-1), and CREB activation was determined by immunoblotting and EMSA. TNFα-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-κB p65 siRNA and/or the NF-κB inhibitor helenalin reduced PDGF-BB- and TNFα-induced cytokine expression, suggesting the involvement of NF-κB signaling. DMF inhibited TNFα-induced NF-κB p65 phosphorylation, NF-κB nuclear entry, and NF-κB-DNA complex formation, whereas PDGF-BB appeared not to activate NF-κB within 60 min. Both stimuli induced the phosphorylation of MSK-1, NF-κB p65 at Ser276, and CREB, and all were inhibited by DMF. These data suggest that DMF downregulates cytokine secretion not only by inhibiting NF-κB but a wider range of NF-κB-linked signaling proteins, which may explain its potential beneficial effect in asthma. Copyright © 2009 the American Physiological Society.
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