Regulation of TNF-alpha-mediated hyperplasia through TNF receptors, TRAFs, and NF-kappaB in synoviocytes obtained from patients with rheumatoid arthritis.
Although the etiology of rheumatoid arthritis (RA) has not been clearly understood to date, the hyperplasia of the synovial membrane imposed by pro-inflammatory cytokines has been suggested to play a crucial role in the progression of this disease. TNF-alpha, a potent pro-inflammatory cytokine, was detected at highly enhanced concentrations in the blood and synovial fluids of patients with RA relative to those of patients with osteoarthritis and normal subjects. To evaluate the role of TNF-alpha in the synovial hyperplasia during the pathogenic state, we investigated cellular outcomes and molecular mechanisms of synoviocytes in response to TNF-alpha. Following TNF-alpha treatment, fibroblast-like synoviocytes (FLS) obtained from patients with RA proliferated, unlike the cells from a normal subject that were unaffected. This TNF-alpha induced proliferation of synoviocytes obtained from RA patients coincided with down-regulation of TNFR1 and up-regulation of TNFR2 and TRAF1-6, as well as NF-kappaB activation. TNF-alpha-induced proliferation of synoviocytes was inhibited by transfection with a dominant negative mutant form of I-kappaBalpha cDNA (I-kappaBalphadN). Moreover, following TNF-alpha treatment, transfectants with I-kappaBalphadN underwent apoptosis, whereas mock-transfectants did not. Taken together, these results suggest that high levels of TNF-alpha present in RA synovium play an important role in the synovial hyperplasia of RA by suppressing apoptosis and promoting proliferation of synoviocytes through NF-kappaB-dependent signaling pathways mediated by up-regulated TNFR2 and TRAF1-6 molecules.
Youn
Jeehee
J
Department of Anatomy and Cell Biology, Institute of Biomedical Science, Hanyang University School of Medicine, Seoul, South Korea.
Kim
Ho-Youn
HY
Park
Ji Hee
JH
Hwang
Sung-Hee
SH
Lee
Soo Young
SY
Cho
Chul-Soo
CS
Lee
Suk Kyeong
SK
D017209:Apoptosis / Q000502:physiology; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006965:Hyperplasia; D016328:NF-kappa B / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D013582:Synovial Fluid / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha