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Interleukin 1 receptor antagonist mediates the beneficial effects of systemic interferon beta in mice: implications for rheumatoid arthritis
  1. Maripat Corr1,
  2. David L Boyle1,
  3. Lisa M Ronacher1,
  4. Brian R Lew1,
  5. Lisa G van Baarsen2,
  6. Paul P Tak2,
  7. Gary S Firestein1
  1. 1Division of Rheumatology, Allergy and Immunology, University of California at San Diego, La Jolla, California, USA
  2. 2Division of Clinical Immunology and Rheumatology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
  1. Correspondence to Dr Maripat Corr, Division of Rheumatology, Allergy and Immunology, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; mcorr{at}ucsd.edu

Abstract

Objectives Interferon beta (IFNβ) therapy is effective in multiple sclerosis and murine models of arthritis. Surprisingly, systemic IFNβ treatment induces only minimal improvement in rheumatoid arthritis (RA). To explain this paradox, the authors evaluated the mechanism of IFNβ benefit in passive K/BxN arthritis and the effect of IFNβ treatment on RA synovium.

Methods Interleukin 10 (IL-10) null, IL-1 receptor antagonist (IL-1Ra) null, IL-1Ra transgenic and wild-type mice were administered K/BxN serum and in some cases treated with IFNβ or normal saline. Clinical response and histological scores were assessed. Gene expression was measured by quantitative PCR. Serum IL-1Ra and IL-6 were measured by ELISA. Paired synovial biopsy specimens from RA patients pre-IFNβ and post-IFNβ treatment (purified natural fibroblast IFNβ (Frone) subcutaneously three times weekly 6 million IU, 12 million IU or 18 million IU) were immunostained for IL-1Ra and IL-10.

Results Il1rn transgenic mice had an attenuated course of arthritis, whereas Il1rn−/− and Il10−/− mice had more severe serum transfer arthritis than wild-type mice. Daily IFNβ treatment significantly decreased arthritis severity in Il10−/− but not Il1rn−/− mice. IFNβ treatment did not reduce the histological scores in Il1rn−/− mice or gene expression of articular cytokines and chemokines. Paired synovial biopsy specimens from RA patients treated with IFNβ demonstrated a trend towards increased IL-1Ra and reduced IL-10 expression on day 85 levels compared with pretreatment specimens.

Conclusions The anti-inflammatory effects of IFNβ in passive K/BxN arthritis are dependent on IL-1Ra, but not IL-10. Systemic IFNβ treatment in RA increases synovial IL-1Ra production, but also decreases IL-10 production.

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Footnotes

  • Funding This work was supported by grants from the Arthritis Foundation and the National Institutes of Health, including R01 AI067752.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the Medical Ethics Committee of the Leiden University Medical Center.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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