Abstract :
[en] 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.
Scopus citations®
without self-citations
37