15-Deoxy-Δ12,14-prostaglandin J2 Inhibits Bay 11-7085-induced Sustained Extracellular Signal-regulated Kinase Phosphorylation and Apoptosis in Human Articular Chondrocytes and Synovial Fibroblasts

Relić, Biserka; Benoît, Valérie; Franchimont, Nathalie; Ribbens, Clio; Kaiser, Marie‐Joëlle; Gillet, Philippe; Merville, Marie‐Paule; Bours, Vincent; Malaise, Michel

doi:10.1074/jbc.m314118200

Cited by 42 publications

(57 citation statements)

References 36 publications

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“…Previous reports have described additional effects of Bay 11 compounds on the ERK, JNK, and p38 MAPK (43). Ligand occupancy of TLRs by their cognate PAMPs activates several wellcharacterized signaling pathways within monocytes and macrophages.…”

Section: Discussionmentioning

confidence: 95%

Potentiation of Caspase-1 Activation by the P2X7 Receptor Is Dependent on TLR Signals and Requires NF-κB-Driven Protein Synthesis

Kahlenberg

Lundberg

Kertesy

et al. 2005

The Journal of Immunology

178

147

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The proinflammatory cytokines IL-1β and IL-18 are inactive until cleaved by the enzyme caspase-1. Stimulation of the P2X7 receptor (P2X7R), an ATP-gated ion channel, triggers rapid activation of caspase-1. In this study we demonstrate that pretreatment of primary and Bac1 murine macrophages with TLR agonists is required for caspase-1 activation by P2X7R but it is not required for activation of the receptor itself. Caspase-1 activation by nigericin, a K+/H+ ionophore, similarly requires LPS priming. This priming by LPS is dependent on protein synthesis, given that cyclohexamide blocks the ability of LPS to prime macrophages for activation of caspase-1 by the P2X7R. This protein synthesis is likely mediated by NF-κB, as pretreatment of cells with the proteasome inhibitor MG132, or the IκB kinase inhibitor Bay 11-7085 before LPS stimulation blocks the ability of LPS to potentiate the activation of caspase-1 by the P2X7R. Thus, caspase-1 regulation in macrophages requires inflammatory stimuli that signal through the TLRs to up-regulate gene products required for activation of the caspase-1 processing machinery in response to K+-releasing stimuli such as ATP.

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Section: Discussionmentioning

confidence: 95%

Potentiation of Caspase-1 Activation by the P2X7 Receptor Is Dependent on TLR Signals and Requires NF-κB-Driven Protein Synthesis

Kahlenberg

Lundberg

Kertesy

et al. 2005

The Journal of Immunology

178

147

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“…Further analysis in synovial fibroblasts showed that only molecules that suppressed BAY 11-7085-induced phosphorylation of ERK (i.e. 15-d-PGJ 2 , PGD 2 , and to a lesser extent, MEK inhibitor U0126, but not PGE 2 and PGF 2· ) were able to protect cells from apoptosis (45). In diosgenin-induced apoptosis in human RA FLS, we showed that p38 inhibitor (SB203580), JNK inhibitor (SP600125) and MEK inhibitor (U0126) decreased diosgenin-induced COX-2 mRNA and protein expression.…”

Section: Discussionmentioning

confidence: 99%

“…Our results showed that apoptosis induced by diosgenin (40 μM) in human RA FLS inhibited NF-κB binding and activated p38 MAPK without increasing 15-d-PGJ 2 synthesis. However, it has been recently shown that the NF-κB inhibitor BAY11-7085, a potent anti-inflammatory drug in rat adjuvant arthritis, induced apoptosis of chondrocytes and human synovial fibroblasts with a rapid and sustained phosphorylation of ERK (45). Further analysis in synovial fibroblasts showed that only molecules that suppressed BAY 11-7085-induced phosphorylation of ERK (i.e.…”

Section: Discussionmentioning

confidence: 99%

MAP kinase subtypes and Akt regulate diosgenin-induced apoptosis of rheumatoid synovial cells in association with COX-2 expression and prostanoid production

Liagre¹,

Léger²,

Vergne-Salle³

et al. 2007

Int J Mol Med

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Abstract. In the present study, we investigated the signalling pathways involved in diosgenin-induced apoptosis in human rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) in vitro with particular interest on Akt and MAPKs activation in relation to arachidonic acid metabolism via COX-2 pathway. MAPK activation was measured by ELISA quantification in diosgenin-treated human RA FLS. Expression of Akt and phospho-Akt was analyzed by Western blot analysis. Nuclear factor-κB (NF-κB) translocation was evaluated by electromobility shift assay. The prostanoid production (COX-2 activity) was measured by quantitative ELISA. Diosgenininduced apoptosis in the presence of MAPK or Akt inhibitors was detected by a quantitative determination of DNA fragmentation. Treatment of human RA FLS with 40 μM diosgenin caused an activation of p38 and JNK and an inhibition of ERK phosphorylation. Akt and NF-κB are potentially required for diosgenin-induced apoptosis in human RA FLS because 40 μM diosgenin abrogated Akt phosphorylation which correlated with an inhibition of NF-κB nuclear translocation. SB203580 and SP600125 (p38 and JNK inhibitors) reduced diosgenininduced DNA fragmentation whereas U0126 and LY294002 (MEK and PI3 kinase/Akt inhibitors) caused an amplification of proapoptotic effect of diosgenin. Diosgenin increased COX-2 activity resulting in PGE 2 and 6-keto-PGF 1· overproduction in human RA FLS. All MAPK inhibitors markedly reduced diosgenin-induced PGE 2 and 6-keto-PGF 1· synthesis except for SP600125 on 6-keto-PGF 1· production. These results provide, for the first time, strong evidence that a combined association implicating a MEK inhibitor (U0126) and diosgenin is the most effective in inducing very strong apoptosis with down-regulation of COX-2 expression and activity in human RA FLS.

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“…We recently showed that PPAR-␥ agonist 15d-PGJ2 protects human synovial fibroblasts from BAY 11-7085-induced apo-ptosis (16). Analysis of PPAR-␥ expression, as described here, showed that synovial fibroblasts constitutively express PPAR-␥1, which is dephosphorylated and degraded during BAY 11-7085-induced apoptosis.…”

mentioning

confidence: 51%

Peroxisome Proliferator-activated Receptor-γ1 Is Dephosphorylated and Degraded during BAY 11-7085-induced Synovial Fibroblast Apoptosis

Relić

Benoît

Franchimont

et al. 2006

Journal of Biological Chemistry

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Peroxisome proliferator-activated receptor-␥ (PPAR-␥) plays a central role in whole body metabolism by regulating adipocyte differentiation and energy storage. Recently, however, PPAR-␥ has also been demonstrated to affect proliferation, differentiation, and apoptosis of different cell types. As we have previously shown that BAY 11-7085-induced synovial fibroblast apoptosis is prevented by PPAR-␥ agonist 15d-PGJ2; the expression of PPAR-␥ in these cells was studied. Both PPAR-␥1 and PPAR-␥2 isoforms were cloned from synovial fibroblast RNA, but only PPAR-␥1 was detected by Western blot, showing constitutive nuclear expression. Within minutes of BAY 11-7085 treatment, a PPAR-␥1-specific band was shifted into a form of higher mobility, suggesting dephosphorylation, as confirmed by phosphatase treatment of cell extracts. Of interest, BAY 11-7085-induced PPAR-␥1 dephosphorylation was followed by PARP and caspase-8 cleavage as well as by PPAR-␥1 protein degradation. PPAR-␥1 dephosphorylation was followed by the loss of PPAR-DNA binding activity ubiquitously present in synovial fibroblast nuclear extracts. Unlike the phosphorylated form, dephosphorylated PPAR-␥1 was found in insoluble membrane cell fraction and was not ubiquitinated before degradation. PPAR-␥1 dephosphorylation coincided with ERK1/2 phosphorylation that accompanies BAY 11-7085-induced synovial fibroblasts apoptosis. 15d-PGJ2, PGD2, and partially UO126, down-regulated ERK1/2 phosphorylation, protected cells from BAY 11-7085-induced apoptosis, and reversed both PPAR-␥ dephosphorylation and degradation. Furthermore, PPAR-␥ antagonist BADGE induced PPAR-␥1 degradation, ERK1/2 phosphorylation, and synovial fibroblasts apoptosis. The results presented suggest an anti-apoptotic role for PPAR-␥1 in synovial fibroblasts. Since apoptotic marker PARP is cleaved after PPAR-␥1 dephosphorylation but before PPAR-␥1 degradation, dephosphorylation event might be enough to mediate BAY 11-7085-induced apoptosis in synovial fibroblasts.

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15-Deoxy-Δ12,14-prostaglandin J2 Inhibits Bay 11-7085-induced Sustained Extracellular Signal-regulated Kinase Phosphorylation and Apoptosis in Human Articular Chondrocytes and Synovial Fibroblasts

Cited by 42 publications

References 36 publications

Potentiation of Caspase-1 Activation by the P2X7 Receptor Is Dependent on TLR Signals and Requires NF-κB-Driven Protein Synthesis

Potentiation of Caspase-1 Activation by the P2X7 Receptor Is Dependent on TLR Signals and Requires NF-κB-Driven Protein Synthesis

MAP kinase subtypes and Akt regulate diosgenin-induced apoptosis of rheumatoid synovial cells in association with COX-2 expression and prostanoid production

Peroxisome Proliferator-activated Receptor-γ1 Is Dephosphorylated and Degraded during BAY 11-7085-induced Synovial Fibroblast Apoptosis

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