NF-κB activation provides the potential link between inflammation and hyperplasia in the arthritic joint

Abstract

The transcription factor NF-B is a pivotal regulator of inf lammatory responses. While the activation of NF-B in the arthritic joint has been associated with rheumatoid arthritis (RA), its significance is poorly understood. Here, we examine the role of NF-B in animal models of RA. We demonstrate that in vitro, NF-B controlled expression of numerous inf lammatory molecules in synoviocytes and protected cells against tumor necrosis factor ␣ (TNF␣) and Fas ligand (FasL) cytotoxicity. Similar to that observed in human RA, NF-B was found to be activated in the synovium of rats with streptococcal cell wall (SCW)-induced arthritis. In vivo suppression of NF-B by either proteasomal inhibitors or intraarticular adenoviral gene transfer of super-repressor IB␣ profoundly enhanced apoptosis in the synovium of rats with SCW-and pristane-induced arthritis. This indicated that the activation of NF-B protected the cells in the synovium against apoptosis and thus provided the potential link between inf lammation and hyperplasia. Intraarticular administration of NF-kB decoys prevented the recurrence of SCW arthritis in treated joints. Unexpectedly, the severity of arthritis also was inhibited significantly in the contralateral, untreated joints, indicating beneficial systemic effects of local suppression of NF-B. These results establish a mechanism regulating apoptosis in the arthritic joint and indicate the feasibility of therapeutic approaches to RA based on the specific suppression of NF-B.

Regulation of p53 by macrophage migration inhibitory factor in inflammatory arthritis

“…Recent studies in human synovial cells confirm the ability of MIF to activate ERK mitogen-activated protein kinase. Nuclear factor B (NF-B) has been shown to influence synovial hypertrophy via the protection of cells from tumor necrosis factor-mediated apoptosis (37). Direct evidence of NF-B activation by MIF is consistently lacking, however (38).…”

Down‐regulation of FLIP sensitizes rheumatoid synovial fibroblasts to Fas‐mediated apoptosis

“…On the other hand, TNF␣ and Fas receptor activation induces NF-B translocation, which leads to increased FLIP expression (35,36). This NF-B loop of Fas signaling may protect cells from Fas-mediated cell death, resulting in proinflammatory and survival, rather than cytotoxic, effects of death receptor stimulation (36)(37)(38). Permissivity to death receptor-induced apoptosis in other cell types has been suggested to depend upon low NF-B and FLIP induction by death ligand activation (39).…”

Increased synovial tissue NF‐κB1 expression at sites adjacent to the cartilage–pannus junction in rheumatoid arthritis

“…Cell stimulation induces degradation of I B, resulting in nuclear translocation of the Rel/NF-B subunits and activation of transcription. Activated Rel/NF-B subunits are abundantly expressed in RA synovial tissue and in experimental models of arthritis (5)(6)(7)(8)(9). In studies involving experimental arthritis, there is evidence to suggest that the Rel/NF-B subunits play distinct roles in the pathogenesis of inflammatory arthritis (10).…”