Comparison of anti-inflammatory potential of four different dibenzocyclooctadiene lignans in microglia; action via activation of PKA and Nrf-2 signaling and inhibition of MAPK/STAT/NF-κB pathways
Version of Record online: 11 NOV 2013
© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Molecular Nutrition & Food Research
Volume 58, Issue 4, pages 738–748, April 2014
How to Cite
Park, S. Y., Bae, Y.-S., Ko, M. J., Lee, S.-J. and Choi, Y.-W. (2014), Comparison of anti-inflammatory potential of four different dibenzocyclooctadiene lignans in microglia; action via activation of PKA and Nrf-2 signaling and inhibition of MAPK/STAT/NF-κB pathways. Mol. Nutr. Food Res., 58: 738–748. doi: 10.1002/mnfr.201300445
- Issue online: 1 APR 2014
- Version of Record online: 11 NOV 2013
- Manuscript Accepted: 30 AUG 2013
- Manuscript Revised: 16 AUG 2013
- Manuscript Received: 25 JUN 2013
- Ministry of Education, Science and Technology. Grant Number: 2012R1A1A3010601
- Dibenzocyclooctadiene lignans;
- Phase II detoxifying/antioxidant enzymes;
- TLR 2/4 agonists
The aim of our study was to determine the signaling pathways associated with the antineuroinflammatory and neuroprotective responses induced by dibenzocyclooctadiene lignans in microglia.
Methods and results
We employed ELISA, gelatin zymography, transient transfection, Western blot, chromatin immunoprecipitation, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) assays to characterize the effects of dibenzocyclooctadiene lignans on microglia. We found that dibenzocyclooctadiene lignans suppress TLR 2/4 agonist-induced pro-inflammatory cytokines and chemokines, PGE2, nitric oxide, reactive oxygen species (ROS), and MMP-9 enzymatic activity through the suppression of MAPK, NF-κB, and JAK-STAT activation. We next demonstrated that dibenzocyclooctadiene lignans induced the expression of phase II detoxifying/antioxidant enzymes and suppressed the iNOS and ROS activation induced by TLR 2/4 agonists. Interestingly, we also found that dibenzocyclooctadiene lignans induced PKA/CREB/Nrf-2 activation in microglia and that activation of phase II detoxifying/antioxidant enzymes via stimulation of the PKA/CREB/Nrf-2 pathway attenuated TLR 2/4 agonist-induced iNOS and ROS activation. Furthermore, dibenzocyclooctadiene lignans protected primary cortical neurons against microglia-mediated neurotoxicity.
Our findings indicate that phase II detoxifying/antioxidant enzymes and their upstream effectors, PKA/CREB/Nrf-2, play a pivotal role in the antineuroinflammatory and neuroprotective effects of dibenzocyclooctadiene lignans in TLR 2/4 agonist-stimulated microglia.