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This Article Full Text Full Text (PDF) All Versions of this Article: 297/2/L326    most recent 90624.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Seidel, P. Articles by Roth, M. PubMed PubMed Citation Articles by Seidel, P. Articles by Roth, M.

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

¹Pulmonary Cell Research, Department of Research and Pneumology, Department of Internal Medicine, University Hospital Basel, Basel, Switzerland; ²Institute of Pharmaceutical Sciences, Department of Pharmaceutical Biology and Biotechnology, University of Freiburg, Freiburg, Germany; and ³Respiratory Research Group, Faculty of Pharmacy and ⁴Discipline of Pharmacology, University of Sydney, Sydney, Australia

Submitted 15 December 2008 ; accepted in final form 14 May 2009

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-B 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 TNF-induced asthma-relevant cytokines and NF-B 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-B p65 siRNA (100 nM), the NF-B inhibitor helenalin (1 µM) before stimulation with PDGF-BB or TNF (10 ng/ml). Cytokine release was measured by ELISA. NF-B, mitogen and stress-activated kinase (MSK-1), and CREB activation was determined by immunoblotting and EMSA. TNF-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-B p65 siRNA and/or the NF-B inhibitor helenalin reduced PDGF-BB- and TNF-induced cytokine expression, suggesting the involvement of NF-B signaling. DMF inhibited TNF-induced NF-B p65 phosphorylation, NF-B nuclear entry, and NF-B-DNA complex formation, whereas PDGF-BB appeared not to activate NF-B within 60 min. Both stimuli induced the phosphorylation of MSK-1, NF-B p65 at Ser276, and CREB, and all were inhibited by DMF. These data suggest that DMF downregulates cytokine secretion not only by inhibiting NF-B but a wider range of NF-B-linked signaling proteins, which may explain its potential beneficial effect in asthma.

mitogen and stress-activated kinase; CREB; DMF anti-inflammatory action; chronic lung inflammation; DMF steroid sparing effect