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

Swiss Med Wkly. 2010 Dec 7;140:w13132. doi: 10.4414/smw.2010.13132. eCollection 2010.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Proliferation / drug effects*
  • Cells, Cultured
  • Dimethyl Fumarate
  • Down-Regulation / drug effects*
  • Fibroblasts / cytology*
  • Fibroblasts / drug effects*
  • Fumarates / pharmacology*
  • Humans
  • Interleukin-6 / metabolism*
  • Lung / cytology
  • NF-kappa B / antagonists & inhibitors*
  • Transcription Factor AP-1 / antagonists & inhibitors*

Substances

  • Fumarates
  • Interleukin-6
  • NF-kappa B
  • Transcription Factor AP-1
  • Dimethyl Fumarate