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.

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RON is a receptor tyrosine kinase of the MET family that is involved in cell proliferationThe human receptor tyrosine kinases MET and RON (MST1R) (and their respective orthologs in other species) form a unique, two-member gene family that encodes proteins with identical modular structure that may perform similar functions. Oncogenic activating mutations of MET were discovered in hereditary renal carcinoma of the papillary type (1, 2) and a variety of common cancers (3). Oncogenic amplification and overexpression of MET were also reported previously (3). The involvement of RON in carcinogenesis is much less understood.We have recently discovered that RON is negatively controlled by the tumor suppressor protein HYAL2 and becomes activated in a ligand-independent mechanism upon HYAL2 removal, leading to cell transformation (4). An oncogenic function of RON was also demonstrated in a transgenic model (5).RON is almost ubiquitously expressed (6 -8) in a variety of normal cell types (6, 9 -14) and also in a number of tumor cell lines (15) in which RON kinase activity is deregulated. The extracellular part of RON is comprised of a sema domain, a PSI 1 domain (plexin semaphorins integrins (16), also known as MRS domain (MET-related sequence) (17)), and four IPT domains (immunoglobulin-like fold shared by plexins and transcription factors (16)). The functional role of these domains remains unknown. The sema domain (whose presence in RON and MET makes them a unique family among the approximate 20 receptor tyrosine kinase families identified by the Human Genome Project) is represented by a block of ϳ500 amino acids with 15 conserved cysteine residues intermingled with stretches of conserved amino acids and a conserved potential glycosylation site (18). This domain is also present in semaphorins and plexins (a class of semaphorin receptors).Secreted semaphorins and their receptors were initially discovered by their ability to induce axon steering and collapse of the growth cone in vitro, but it is now evident their biological function is not confined to the neural system and involves at least the immune (19,20), cardiovascular, and skeletal systems (21) in vertebrates. Semaphorins are also overexpressed in metastasizing cancer cells (22,23), possibly facilitating cell dissociation and survival. Because the sema domain of semaphorins mediates receptor specificity (24), we reasoned that the sema domain of RON might contain the ligand-binding region.In this study, we show that two soluble molecules designed over the sema and sema ϩ PSI domains of RON (referred to as "ron-sema" and "ron-PSI," respectively) undergo correct posttranslational processing and are secreted when expressed in mammalian cells. Both molecules inhibit ligand binding to the RON receptor (both ␣-and ␤-MSP-binding sites), indicating that the RON sema domain may contain the ligand-binding sites and mediate ligand-binding specificity. In addition, we found that these secreted soluble molecules have a highly specific dominant-negative effect on RON kinase acti...