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Synergistic benefit in inflammatory arthritis by targeting IκB kinase ϵ and interferon β
  1. M Corr,
  2. D L Boyle,
  3. L Ronacher,
  4. N Flores,
  5. G S Firestein
  1. Division of Rheumatology, Allergy and Immunology, University of California, San Diego, La Jolla, California, USA
  1. M Corr, Division of Rheumatology, Allergy and Immunology, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093–0663, USA; mcorr{at}ucsd.edu

Abstract

Objectives: The IκB kinase (IKK)-related kinase IKKϵ regulates type I interferon expression and responses as well as proinflammatory mediator production. We examined the role of IKKϵ in arthritis and its ability to enhance the therapeutic response to systemic interferon (IFN) β therapy in passive murine K/BxN arthritis.

Methods: IKKϵ–/–, IFNαβR–/– and wild type mice were given K/BxN serum and treated with polyinosinic polycytidylic acid (poly(I:C)), IFNβ, or normal saline. Clinical response and histological scores were assessed. Gene expression in the paws was measured by quantitative PCR. Serum interleukin 1a receptor agonist (IL1Ra) and IL10 were measured by ELISA and multiplex bead array.

Results: Arthritis was almost completely blocked in wild type mice if arthritogenic K/BxN serum and the Toll-like receptor (TLR)3 ligand, poly(I:C), were coadministered at the onset of the model, but not in established disease. Mice deficient in IFNαβR had an accelerated course of arthritis, and did not respond to poly(I:C). IKKϵ null mice had a modest decrease in clinical arthritis compared with heterozygous mice. Low doses of IFNβ that were ineffective in wild type mice significantly decreased clinical arthritis in IKKϵ null mice. Articular chemokine gene expression was reduced in the IKKϵ–/– mice with arthritis and secreted IL1Ra (sIL1Ra) mRNA was significantly increased. Serum levels of IL1Ra were increased in low dose IFNβ-treated IKKϵ–/– mice.

Conclusions: Subtherapeutic doses of IFNβ enhance the anti-inflammatory effects of IKKϵ deficiency, possibly by increasing production of IL1Ra and unmasking the antichemokine effects. Combination therapy with low dose IFNβ and an IKKϵ inhibitor might improve efficacy of either agent alone and offers a novel approach to RA.

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Footnotes

  • Competing interests: None declared.

  • Funding: This work was supported by grants from the US National Institutes for Health (NIH), including R01 AI067752.

  • See Editorial, p 157

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