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See detailTNF-alpha protects human primary articular chondrocytes from nitric oxide-induced apoptosis via nuclear factor-kappaB
Relic, Biserka ULg; Bentires-Alj, Mohamed; Ribbens, Clio ULg et al

in Laboratory Investigation : Journal of Technical Methods & Pathology (2002), 82(12), 1661-1672

TNF-alpha plays a key role in rheumatoid arthritis, but its effect on chondrocyte survival is still conflicting. In the present study, we tested how TNF-alpha influences chondrocyte survival in response ... [more ▼]

TNF-alpha plays a key role in rheumatoid arthritis, but its effect on chondrocyte survival is still conflicting. In the present study, we tested how TNF-alpha influences chondrocyte survival in response to nitric oxide (NO)-related apoptotic signals, which are abundant during rheumatoid arthritis. Human primary articular chondrocytes or cartilage explants were pretreated with TNF-alpha for 24 hours and then treated with the proapoptotic NO donor sodium-nitro-prusside (SNP) for an additional 24 hours. TNF-alpha pretreatment markedly protected chondrocytes from SNP-induced cell death. Preincubation of chondrocytes with TNF-alpha inhibited both SNP-induced high-molecular weight DNA fragmentation and annexin V-FITC binding. Of interest, TNF-alpha induced persistent nuclear factor-kappaB (NF-kappaB)-DNA binding activity even in the presence of SNP, mirroring apoptosis protection effects. Both the TNF-alpha antiapoptotic effect and NF-kappaB-DNA binding activity were significantly inhibited by NF-kappaB inhibitors, Bay 11-7085, MG-132, and adenovirus-expressing mutated IkappaB-alpha. Phosphatidylinositol-3 kinase inhibitor LY 294002 also markedly inhibited the antiapoptotic effect of TNF-alpha. In primary chondrocytes, TNF-alpha induced expression of the antiapoptotic protein Cox-2, which persisted in the presence of SNP, and a specific Cox-2 inhibitor significantly blocked the TNF-alpha protective effect. We therefore conclude that TNF-alpha-mediated protection of chondrocytes from NO-induced apoptosis acts through NF-kappaB and requires Cox-2 activity. [less ▲]

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