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.
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.
Department of Orthopedic Surgery, University of Liège, Liège, 4000 Belgium.
Biserka
B
Relic
Valérie
V
Benoit
Nathalie
N
Franchimont
Clio
C
Ribbens
Marie-Joelle
MJ
Kaiser
Philippe
P
Gillet
Marie-Paule
MP
Merville
Vincent
V
Bours
Michel G
MG
Malaise
D017304:Annexin A5 / Q000494:pharmacology; D000890:Anti-Infective Agents / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D002356:Cartilage / Q000166:cytology; D002358:Cartilage, Articular / Q000166:cytology*; D002470:Cell Survival; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D004396:Coloring Agents / Q000494:pharmacology; D003546:Cysteine Endopeptidases; D015237:Dinoprost / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007155:Immunologic Factors / Q000502:physiology; D007976:Leupeptins / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009570:Nitriles; D010766:Phosphorylation; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists; D013450:Sulfones; D013583:Synovial Membrane / Q000166:cytology*; D045162:Thiazolidinediones / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D017304:Annexin A5; D000890:Anti-Infective Agents; C416282:BAY 11-7085; D004396:Coloring Agents; D020672:I-kappa B Proteins; D007155:Immunologic Factors; D007976:Leupeptins; D009097:Multienzyme Complexes; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606206:Nfkbia protein, rat; D009570:Nitriles; D018160:Receptors, Cytoplasmic and Nuclear; D013450:Sulfones; D045162:Thiazolidinediones; D014157:Transcription Factors; D000072000:NF-KappaB Inhibitor alpha; D015237:Dinoprost; D020928:Mitogen-Activated Protein Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D015232:Dinoprostone; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D015230:Prostaglandin D2; C039671:ciglitazone