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IFN-β for the treatment of rheumatoid arthritis?
Arthritis Res Ther volume 5, Article number: 34 (2003)
IFN-β is emerging as a pivotal molecule involved in synovial inflammation and bone homeostasis. We conducted in vitro studies as well as studies using the collagen-induced arthritis model to investigate the effects of IFN-β.
DBA/1 male mice were immunized intradermally with bovine type II collagen in complete Freund's adjuvant. On the first clinical sign of disease, mice were treated for 7 days by daily intraperitoneal injections of recombinant mouse IFN-β or saline. Disease progression was monitored by validated visual clinical scoring and by measurement of paw swelling using calipers. Inflammation and joint destruction were assessed histologically 8 days after the onset of arthritis on decalcified wax-embedded paw sections and quantified. Safranin O staining was performed to determine proteoglycan depletion. In addition, cytokine profiles in the synovium were evaluated by immunohistochemistry. Cytokine expression was also measured in supernatants of rheumatoid arthritis (RA) and osteoarthritis fibroblast-like synoviocytes (FLS) in culture after incubation with IFN-β. We incubated RA FLS, which were transfected with a NF-κB/luciferase construct, with IFN-β and measured luciferase activity to determine the effects on NF-κB activity.
In two independent experiments with eight to 10 mice per treatment group in each experiment, IFN-β at doses from 0.25 μg/injection and higher significantly reduced disease severity. Moreover, IFN-β-treated animals had significantly less cartilage and bone destruction than control animals, demonstrating a protective effect of the treatment. There was a significant reduction in c-Fos expression and osteoclast numbers. The proinflammatory cytokines tumor necrosis factor alpha and IL-6 were significantly reduced, and IL-10 production was increased after IFN-β treatment. In vitro studies revealed reduced NF-κB activity and expression of proinflammatory cytokines in RA FLS after IFN-α treatment.
Taken together, our data show that frequent exogenous administration of IFN-β protein may reduce synovial inflammation and protects against cartilage and bone destruction by inhibition of NF-κB activity, immunomodulation, and impairment of osteoclastogenesis through inhibition of c-Fos. Continuous IFN-β expression at the site of inflammation may be required to reach these therapeutic effects in RA patients. The exciting biological effects could translate into clinically meaningful improvement if the cytokine is administered frequently, when pegylated IFN-β is used, or when IFN-β gene therapy is used. Therefore, IFN-β gene therapy studies are now underway.
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Tak, P., Holten, J.v., Reedquist, K. et al. IFN-β for the treatment of rheumatoid arthritis?. Arthritis Res Ther 5, 34 (2003) doi:10.1186/ar835
- Synovial Inflammation
- Reduce Disease Severity
- Cytokine Tumor Necrosis Factor
- Daily Intraperitoneal Injection
- Gene Therapy Study