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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, METHODS, RESULTS. Meshes: Apoptosis, CASP8 and FADD-Like Apoptosis Regulating Protein, Carrier Proteins, Cartilage, Articular, Caspase 3, Caspase 8, Caspase Inhibitors, Caspases, Cells, Cultured, Chondrocytes, Dose-Response Relationship, Drug, Fas Ligand Protein, Flow Cytometry, Humans, Interferon-gamma, Intracellular Signaling Peptides and Proteins, Membrane Glycoproteins, Osteoarthritis, Knee, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, fas Receptor.
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Is inhibition of CD95 apoptotic signaling by interferon-gamma in human osteoarthritic chondrocytes associated with increased expression of FLICE inhibitory protein? Context: Cartilage homeostasis dysregulation during osteoarthritis (OA) has been linked to an increased rate of apoptosis of chondrocytes, the only cell type resident in the cartilage. In addition, the CD95-CD95 ligand (the Fas system) has emerged as one of the major pathways of cell death in the cartilage. We undertook the present study to investigate the role of interferon-gamma (IFNgamma) in the regulation of the Fas system by analyzing the modulation of intracellular signaling molecules (FLICE inhibitory protein [FLIP] and caspases 3 and 8) in primary cultures of human OA chondrocytes. CD95-induced apoptotic death of human OA chondrocytes was analyzed in the presence or absence of IFNgamma using cell death immunoassay for apoptosis, real-time polymerase chain reaction for FLIP and caspase 8 expression, Western blotting for FLIP, and proteolytic activity for caspases 3 and 8. CD95-induced apoptotic death of human OA chondrocytes was strongly counteracted by IFNgamma treatment, although the surface expression of CD95 was slightly up-regulated by this cytokine. The messenger RNA (mRNA) expression of FLIP and caspase 8, mediators involved in CD95 signaling, revealed that FLIP expression in human OA chondrocytes was significantly up-regulated (2-fold increase) by IFNgamma treatment. Moreover, the FLIP:caspase 8 mRNA ratio increased significantly. FLIP up-regulation by IFNgamma was confirmed at the protein level. Caspase 8 and caspase 3 proteolytic activities, both induced in these cells by stimulation with anti-CD95, were also significantly down-modulated by IFNgamma.
assistant
These findings suggest that IFNgamma impairs CD95-mediated signaling and apoptotic death in human chondrocytes. Its mechanism of action involves down-regulation of caspase 8 and caspase 3 activities and increased expression of the antiapoptotic protein FLIP, suggesting an interesting mechanism for the inhibition of chondrocyte apoptosis. Final Decision: yes