S. Yamasaki et al., Importance of NF-kappa B in rheumatoid synovial tissues: in situ NF-kappa B expression and in vitro study using cultured synovial cells, ANN RHEUM D, 60(7), 2001, pp. 678-684
Objectives-To examine whether inhibition of NF-kappaB induces apoptosis of
human synovial cells stimulated by tumour necrosis factor alpha (TNF alpha)
, interieukin 1 beta (IL1 beta), and anti-Fas monoclonal antibody (mAb).
Methods-The expression of proliferating cell nuclear antigen (PCNA), NF-kap
paB, and the presence of apoptotic synovial cells were determined in synovi
al tissues. Apoptosis of cultured synovial cells was induced by inhibition
of NF-kappaB nuclear translocation by Z-Leu-Leu-Leu-aldehyde (LLL-CHO). The
activation of caspase-3 and expression of XIAP and cIAP2 in synovial cells
in LLL-CHO induced apoptosis was also examined.
Results-Abundant PCNA+ synovial cells were found in rheumatoid arthritis (R
A) synovial tissue, though a few apoptotic synovial cells were also detecte
d in the RA synovial tissues. Nuclear NF-kappaB was expressed in RA synovia
l cells. Electrophoretic mobility shift assay showed that treatment of cell
s with TNF alpha or IL1 beta significantly stimulated nuclear NF-kappaB act
ivity. A small number of apoptotic synovial cells expressing intracellular
active caspase-3 were found after treatment of cells with LLL-CHO. Although
treatment of RA synovial cells with TNF alpha or IL1 beta alone did not in
duce apoptosis, apoptosis induced by LLL-CHO and caspase-3 activation were
clearly enhanced in TNF alpha or IL1 beta stimulated synovial cells compare
d with unstimulated synovial cells. Furthermore, induction of apoptosis of
synovial cells with caspase-3 activation by anti-Fas mAb was clearly increa
sed by LLL-CHO. The expression of cIAP2 and XIAP in synovial cells may not
directly influence the sensitivity of synovial cells to apoptosis induced b
y LLL-CHO.
Conclusion-The results suggest that NF-kappaB inhibition may be a potential
ly important therapeutic approach for RA by correcting the imbalance betwee
n apoptosis and proliferation of synovial cells in RA synovial tissue.