Inhibition of NF-κB and AP-1 by dimethylfumarate correlates with down-regulated IL-6 secretion and proliferation in human lung fibroblasts.
QUESTION UNDER STUDY/PRINCIPLES: Dimethylfumarate (DMF) had been reported to reduce asthma symptoms and to improve the quality of life of asthma patients. Therefore, we assessed the anti-inflammatory and anti-remodeling effect of DMF on isolated lung fibroblasts, which are relevant to inflammatory lung diseases. We determined the effect of DMF on platelet derived growth factor (PDGF)-BB induced proliferation, as well as on PDGF-BB and tumor necrosis factor (TNF)-α induced interleukin (IL)-6 secretion and on activation of activated protein (AP)-1 and nuclear factor kappaB (NF-ĸB).


METHODS
Confluent lung fibroblasts were incubated with DMF (0.1-100 μM) 1 hour before stimulation with PDGF-BB or TNF-α (both 10 ng/ml). IL-6 secretion was measured by ELISA. NF-ĸB and AP-1 activation was determined by immuno-blotting and EMSA. Cell proliferation was assessed by [3H]-thymidine incorporation in subconfluent fibroblasts.


RESULTS
PDGF-BB but not TNF-α induced fibroblast proliferation. This was dose dependently reduced by DMF in a concentration range of 10-100 μM. PDGF-BB and TNF-α induced IL-6 secretion by lung fibroblasts and this was inhibited by DMF in a dose-dependent manner. However, PDGF-BB induced IL-6 secretion did not correlate with NF-ĸB activity, while TNF-α did. DMF inhibited the TNF-α induced NF-ĸB-DNA binding, but had neither an inhibitory effect on NF-ĸB nuclear entry nor on the degradation of IκB-α. PDGF-BB and TNF-α activated AP-1, which was also inhibited by DMF.


CONCLUSIONS
Our data suggest that DMF down-regulates TNF-α-induced IL-6 secretion and proliferation by inhibiting NF-ĸB and AP-1 activity, indicating its potential beneficial use for the treatment of inflammatory lung diseases.
Pulmonary Cell Research, Department of Biomedicine and Pneumology, University Hospital Basel, Switzerland.
Petra
P
Seidel
Irmgard
I
Merfort
Michael
M
Tamm
Michael
M
Roth
D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D000069462:Dimethyl Fumarate; D015536:Down-Regulation / Q000187:drug effects*; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects*; D005650:Fumarates / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008168:Lung / Q000166:cytology; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors*
D005650:Fumarates; D015850:Interleukin-6; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D000069462:Dimethyl Fumarate