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Treatment with recombinant interferon-β reduces inflammation and slows cartilage destruction in the collagen-induced arthritis model of rheumatoid arthritis

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Abstract

We investigated the therapeutic potential and mechanism of action of IFN-β 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-β 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-κB 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-β. We also examined the effect of IFN-β on NF-κB activity. IFN-β, at 0.25 μg/injection and higher, significantly reduced disease severity in two experiments, each using 8–10 mice per treatment group. IFN-β-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-κB ligand and c-Fos. Tumor necrosis factor α and IL-6 expression were significantly reduced, while IL-10 production was increased after IFN-β treatment. IFN-β reduced expression of IL-6, IL-8, and GM-CSF in RA and osteoarthritis fibroblast-like synoviocytes, correlating with reduced NF-κB activity. The data support the view that IFN-β is a potential therapy for RA that might help to diminish both joint inflammation and destruction by cytokine modulation.

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Abbreviations

BSA:

bovine serum albumin

CIA:

collagen-induced arthritis

DMEM:

Dulbecco's modified Eagle's medium

ELISA:

enzyme-linked immunosorbent assay

FCS:

fetal calf serum

FLS:

fibroblast-like synoviocytes

GM-CSF:

granulocyte/macrophage-colony-stimulating factor

HRP:

horseradish peroxidase

IFN:

interferon

IL:

interleukin

MHC:

major histocompatibility complex

NF:

nuclear factor

OA:

osteoarthritis

PBS:

phosphate-buffered saline

RA:

rheumatoid arthritis

RANKL:

receptor activator of NF-κB ligand

TNF:

tumor necrosis factor.

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Authors and Affiliations

  1. Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, F4-218, Academic Medical Center, PO Box 22700, 1100, DE, Amsterdam, The Netherlands

    Judith van Holten, Kris Reedquist, Tom JM Smeets, Margriet J Vervoordeldonk & Paul P Tak

  2. Serono Pharmaceutical Research Institute, Geneva, Switzerland

    Pascale Sattonet-Roche & Christine Plater-Zyberk

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  1. Judith van Holten
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  2. Kris Reedquist
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  3. Pascale Sattonet-Roche
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  4. Tom JM Smeets
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  5. Christine Plater-Zyberk
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Correspondence to Paul P Tak.

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Competing interests

Dr Tak has received support from Serono for a separate clinical study investigating the use of interferon-β in rheumatoid arthritis patients. Mrs Sattonet-Roche is an employee of Serono. Dr Plater-Zyberk is a former employee of Serono. Dr van Holten has received a research grant from the Serono Pharmaceutical Research Institute.

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van Holten, J., Reedquist, K., Sattonet-Roche, P. et al. Treatment with recombinant interferon-β reduces inflammation and slows cartilage destruction in the collagen-induced arthritis model of rheumatoid arthritis. Arthritis Res Ther 6, R239 (2004). https://doi.org/10.1186/ar1165

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