title: Interleukin 1 receptor antagonist mediates the beneficial effects of systemic interferon beta in mice: implications for rheumatoid arthritis.
abstract: OBJECTIVE
  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.
authors.affiliation: 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@ucsd.edu
authors.forename: Maripat
authors.initials: M
authors.lastname: Corr
authors.forename: David L
authors.initials: DL
authors.lastname: Boyle
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Ronacher
authors.forename: Brian R
authors.initials: BR
authors.lastname: Lew
authors.forename: Lisa G
authors.initials: LG
authors.lastname: van Baarsen
authors.forename: Paul P
authors.initials: PP
authors.lastname: Tak
authors.forename: Gary S
authors.initials: GS
authors.lastname: Firestein
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D018836:Inflammation Mediators / Q000378:metabolism; D016899:Interferon-beta / Q000627:therapeutic use*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D016753:Interleukin-10 / Q000096:biosynthesis / Q000502:physiology; D015850:Interleukin-6 / Q000097:blood; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D013583:Synovial Membrane / Q000276:immunology; D017211:Treatment Failure
chemical_list: D018501:Antirheumatic Agents; D016207:Cytokines; C507764:Il1rn protein, mouse; D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D015850:Interleukin-6; D016753:Interleukin-10; D016899:Interferon-beta; D019278:Matrix Metalloproteinase 3; C511769:Mmp3 protein, mouse