Abstract
The pathogenesis of rheumatoid arthritis (RA) evolves from deregulated cellular and humoral immunity resulting in a chronic and systemic inflammatory response. Perpetuating the sustained inflammation in RA synovial joints requires the migration and retention of activated T-lymphocytes, B-lymphocytes, mast cells, neutrophils and antigen presenting cells. The synovial tissue becomes hyperplastic as a result of unrestrained synoviocyte proliferation and the resistance of synoviocytes, immune and inflammatory cells to apoptosis. Synoviocyte proliferation is mainly sustained by the elevated levels of pro-inflammatory cytokines in the RA synovial joint milieu. Thus, proinflammatory cytokines, including tumor necrosis factor-α, interleukin-(IL)-1β and IL-6, IL-17, interferon-γ, among others, predominantly activate the stress-activated protein kinase/mitogen-activated protein kinase (SAPK/MAPK) and the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathways which are known to cause the induction of apoptosis. However, activation of SAPK/MAPK and/or JAK/STAT pathways can also cause ‘cross-talk’ and activation of the phosphatidylinositol-3-kinase/Akt pathway which generally results in aberrant cell survival. The synovial tissue of RA synovial joints is also characterized by elevated levels of antiapoptosis proteins which suppress the apoptotic response. One of the main clinical responses of RA patients to therapy with methotrexate, sulfasalzine and leflunomide, or disease-modifying anti-rheumatic biological drugs, such as antagonists of tumor necrosis factor-α and the IL-6 receptor is actually to suppress the activation of signal transduction that inhibit apoptosis thereby reducing the survival of T- and B-cells, macrophages and inflammatory cells. In addition, several novel experimental strategies are also being considered with the view towards neutralizing those molecules held responsible for the resistance of synovial tissue to apoptosis. Thus, stimulating apoptosis may ameliorate arthritis. These targets include a group of tumor necrosis factor-related proteins, the BH3-only bcl-2 proteins, Fas ligand, cytokines such as IL-17 and IL-19, p53 up-regulated modulator of apoptosis and survivin.
Highlights
Dysfunctional cellular and humoral immunity are two of the signature features of rheumatoid arthritis (RA) [1-3]
Restoring Fas/Fas ligand (FasL) responsiveness of these cells either by directly altering the defective sequence of cellular events resulting in correcting Fas/FasL-deficient apoptosis or by experimental manipulation of other pathways involved in Fas/FasL activation may prove to be beneficial as a novel therapeutic target for suppressing RA synovial tissue hyperplasia
Dyndra et al [86] showed that the transfer of a tissue inhibitor of metalloproteinases-3 (TIMP-3) gene construct into RA synovial fibroblasts (RASF) or into the MRC-5 human lung fetal fibroblast cell line completely reversed the dampening effect of tumor necrosis factor-α (TNF-α) on Fas/FasL-induced apoptosis, inhibited TNF-α-induced NF-κB activation and suppressed TNF-α-mediated up-regulation of soluble Fas
Summary
Dysfunctional cellular and humoral immunity are two of the signature features of rheumatoid arthritis (RA) [1-3]. In other gene therapy studies, Yao et al [40] showed that adenoviral-expressing TRAIL (Ad.TRAIL) induced apoptosis in the proliferating synovium in a rabbit model of arthritis while reducing markers of synovial tissue inflammation.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
