Regulation of inflammation signalling by resveratrol in human chondrocytes in vitro.
The inflammatory process plays a pivotal role during the pathogenesis of osteoarthritis, dominated by catabolic processes initiated by pro-inflammatory cytokines such as IL-1beta. Resveratrol, a natural phytoalexin occurring in various fruits has previously been shown to exhibit anti-inflammatory properties in several cell types. We investigated, whether resveratrol may be a useful blocker of pro-inflammatory cytokine signalling pathways in arthritis. We first examined the effects of resveratrol on the proliferation and production of IL-1beta in primary human articular chondrocytes treated with IL-1betain vitro. Resveratrol reversed significantly IL-1beta-reduced cell proliferation and blocked IL-1beta-stimulated cell membrane bound- and mature IL-1beta synthesis in chondrocytes. Furthermore, resveratrol was able to inhibit the IL-1beta-induced degradation of mitochondria and apoptosis in chondrocytes in a time-dependent manner. Because caspase inhibitor Z-DEVD-FMK abolished the IL-1beta-induced apoptosis in chondrocytes, we examined the effect of resveratrol on the caspase pathway and found that resveratrol blocked the cysteine protease caspase-3 and subsequent cleavage of the DNA repair enzyme PARP. Additionally, resveratrol reversed the IL-1beta-induced up-regulation of reactive oxygen species (ROS) in chondrocytes. Finally, we show that resveratrol induced ubiquitin-independent degradation of tumor suppressor gene protein p53 and inhibited p53-induced apoptosis in chondrocytes in a dose-dependent manner. Our results indicate that resveratrol seems to be an effective in vitro anti-inflammatory agent and has a chondroprotective capacity through suppression of (1) IL-1beta- (2) ROS- and (3) tumor suppressor protein p53-production. Further studies should be undertaken to define a possible implication of resveratrol in osteoarthritis therapy and cartilage tissue engineering.
Csaki
Constanze
C
Ludwig-Maximilians-University Munich, Faculty of Medicine, Institute of Anatomy, Pettenkoferstrasse 11, Munich, Germany.
Keshishzadeh
Nerses
N
Fischer
Karoline
K
Shakibaei
Mehdi
M
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013267:Stilbenes / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D053583:Interleukin-1beta; D013267:Stilbenes; D016159:Tumor Suppressor Protein p53; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D000077185:Resveratrol