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Original article

Vol. 140 No. 4950 (2010)

Inhibition of NF-κB and AP-1 by dimethylfumarate correlates with down-regulated IL-6 secretion and proliferation in human lung fibroblasts

  • P Seidel
  • I Merfort
DOI
https://doi.org/10.4414/smw.2010.13132
Cite this as:
Swiss Med Wkly. 2010;140:w13132
Published
06.12.2010

Summary

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.

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