title: Treatment with recombinant interferon-beta reduces inflammation and slows cartilage destruction in the collagen-induced arthritis model of rheumatoid arthritis.
abstract: We investigated the therapeutic potential and mechanism of action of IFN-beta protein for the treatment of rheumatoid arthritis (RA). Collagen-induced arthritis was induced in DBA/1 mice. At the first clinical sign of disease, mice were given daily injections of recombinant mouse IFN-beta or saline for 7 days. Disease progression was monitored by visual clinical scoring and measurement of paw swelling. Inflammation and joint destruction were assessed histologically 8 days after the onset of arthritis. Proteoglycan depletion was determined by safranin O staining. Expression of cytokines, receptor activator of NF-kappaB ligand, and c-Fos was evaluated immunohistochemically. The IL-1-induced expression of IL-6, IL-8, and granulocyte/macrophage-colony-stimulating factor (GM-CSF) was studied by ELISA in supernatant of RA and osteoarthritis fibroblast-like synoviocytes incubated with IFN-beta. We also examined the effect of IFN-beta on NF-kappaB activity. IFN-beta, at 0.25 microg/injection and higher, significantly reduced disease severity in two experiments, each using 8-10 mice per treatment group. IFN-beta-treated animals displayed significantly less cartilage and bone destruction than controls, paralleled by a decreased number of positive cells of two gene products required for osteoclastogenesis, receptor activator of NF-kappaB ligand and c-Fos. Tumor necrosis factor alpha and IL-6 expression were significantly reduced, while IL-10 production was increased after IFN-beta treatment. IFN-beta reduced expression of IL-6, IL-8, and GM-CSF in RA and osteoarthritis fibroblast-like synoviocytes, correlating with reduced NF-kappaB activity. The data support the view that IFN-beta is a potential therapy for RA that might help to diminish both joint inflammation and destruction by cytokine modulation.
authors.affiliation: Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, The Netherlands.
authors.forename: Judith
authors.initials: J
authors.lastname: van Holten
authors.forename: Kris
authors.initials: K
authors.lastname: Reedquist
authors.forename: Pascale
authors.initials: P
authors.lastname: Sattonet-Roche
authors.forename: Tom J M
authors.initials: TJ
authors.lastname: Smeets
authors.forename: Christine
authors.initials: C
authors.lastname: Plater-Zyberk
authors.forename: Margriet J
authors.initials: MJ
authors.lastname: Vervoordeldonk
authors.forename: Paul P
authors.initials: PP
authors.lastname: Tak
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000139:chemically induced* / Q000517:prevention & control*; D001172:Arthritis, Rheumatoid / Q000473:pathology*; D002356:Cartilage / Q000187:drug effects / Q000473:pathology; D002357:Cartilage Diseases / Q000517:prevention & control; D024043:Collagen Type II / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000517:prevention & control; D007370:Interferon Type I / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D010003:Osteoarthritis / Q000473:pathology / Q000517:prevention & control; D011994:Recombinant Proteins; D013583:Synovial Membrane / Q000473:pathology
chemical_list: D018501:Antirheumatic Agents; D024043:Collagen Type II; D016207:Cytokines; D007370:Interferon Type I; D011994:Recombinant Proteins