An investigation of cell proliferation and soluble mediators induced by interleukin 1 beta in human synovial fibroblasts: comparative response in osteoarthritis and rheumatoid arthritis

Objectives and Design: The difference in cell proliferation and release of soluble factors in response to interleukin 1 beta (IL-1 beta) in fibroblast s obtained from patients with osteoarthritis (OA) and rheumatoid arthritis (RA) and from normal skin has been investigated. Treatment: The cells were treated with recombinant IL-1 beta in the presence or absence of pharmacolo gical agents for 24 h or 48 h. Methods: Cell proliferation was examined by WST-1 assay, and the amounts of interleukin-6 (IL-6), interleukin-8 (IL-8), macrophage colony stimulating factor (M-CSF), vascular endothelial growth factor (VEGF), matrix metallopr oteinase-l (MMP-1), and prostaglandin E-2 (PGE(2)) were measured by enzyme linked immunosorbent assay (ELISA). Results: IL-1 beta dose-dependently enhanced the proliferation of all fibro blasts. The proliferative response to IL-1 beta in RA synovial fibroblasts was greater than that in OA synovial and skin fibroblasts. However, there w as no difference in spontaneous levels of soluble factors between OA and RA fibroblasts, though medium concentrations of IL-1 beta -released VEGF, MMP -1, and PGE(2), but not cytokines, in RA were slightly higher than those in OA. Ability to release soluble mediators was pronouncedly increased at 3 h to 9 h after stimulating fibroblasts with IL-1 beta for Ih. The proliferat ive response to IL-1 beta in all fibroblasts was inhibited by dexamethasone and the NF-kappaB inhibitor hymenialdisine but not the cyclooxygenase 2 (C OX-2) inhibitor NS-398. But PGE(2) prevented proliferation of RA fibroblast s when added to medium up to 3 h after IL-1 beta stimulation. Dexamethasone also inhibited the release of IL-6, IL-8, and PGE(2) induced by IL-1 beta in both OA and RA fibroblasts. NS-398 exhibited an inhi- bition of IL-1 bet a -induced IL-6 production as well as PGE(2) production. Hymenialdisine inh ibited IL-6 production and reduced IL-8 production dependent on synovial ce ll strains. Methotrexate had no effect on the response to IL-1 beta in syno vial fibroblasts. Conclusion: The present results indicate that the activation of NF-kappaB p lays an important role in the proliferative response to IL-1 beta in human fibroblasts, and suggest that PGE(2) acts as a modulator of cell proliferat ion in inflamed synovial tissue. It appears that the ability to produce sol uble factors in RA synovial fibroblasts is not intrinsic. However, the resp onse to IL-1 beta in RA cells seems to be greater than that in OA cells.