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15-deoxy-delta12,14-prostaglandin J2 Inhibits Bay 11-7085-induced Sustained Extracellular Signal-Regulated Kinase Phosphorylation and Apoptosis in Human Articular Chondrocytes and Synovial Fibroblasts

15-deoxy-delta12,14-prostaglandin J2 Inhibits Bay 11-7085-induced Sustained Extracellular Signal-Regulated Kinase Phosphorylation and Apoptosis in Human Articular Chondrocytes and Synovial Fibroblasts

Biserka Relic, Valérie Benoit, Nathalie Franchimont, Clio Ribbens, Marie-Joelle Kaiser, Philippe Gillet, Marie-Paule Merville, Vincent Bours, Michel G Malaise

J Biol Chem. 2004 May 21;279(21):22399-403.

PMID: 15004016

Abstract:

We have previously shown that nuclear factor-kappaB inhibition by adenovirus expressing mutated IkappaB-alpha or by proteasome inhibitor increases human articular chondrocytes sensibility to apoptosis. Moreover, the nuclear factor-kappaB inhibitor BAY11-7085, a potent anti-inflammatory drug in rat adjuvant arthritis, is itself a proapoptotic agent for chondrocytes. In this work, we show that BAY 11-7085 but not the proteasome inhibitor MG-132 induced a rapid and sustained phosphorylation of extracellular signal-regulated kinases (ERK1/2) in human articular chondrocytes. The level of ERK1/2 phosphorylation correlated with BAY 11-7085 concentration and chondrocyte apoptosis. 15-Deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2) and its precursor prostaglandin (PG) D2 but not PGE2 and PGF2alpha rescued chondrocytes from BAY 11-7085-induced apoptosis. 15d-PGJ2 markedly inhibited BAY 11-7085-induced phosphorylation of ERK1/2. BAY 11-7085 also induced ERK1/2 phosphorylation and apoptosis in human synovial fibroblasts, and these reactions were down-regulated by 15d-PGJ2. Further analysis in synovial fibroblasts showed that only molecules that suppressed BAY 11-7085-induced phosphorylation of ERK1/2 (i.e. 15d-PGJ2, PGD2, and to a lesser extent, MEK1/2 inhibitor UO126, but not prostaglandins E2 and F2alpha or peroxisome proliferator-activated receptor-gamma agonist ciglitazone) were able protect cells from apoptosis. These results suggested that the antiapoptotic effect of 15d-PGJ2 on chondrocytes and synovial fibroblasts might involve inhibition of ERK1/2 phosphorylation.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP196309769	Bay 11-7085		196309-76-9	Price

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