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Synergistic benefit in inflammatory arthritis by targeting IKK∊ and IFNβ
  1. Maripat Corr (mcorr{at}
  1. University of California San Diego, United States
    1. David L. Boyle (dboyle{at}
    1. University of California, San Diego, United States
      1. Lisa Ronacher (lronacher{at}
      1. University of California, San Diego, United States
        1. Nicole Flores (niflores{at}
        1. University of California, San Diego, United States
          1. Gary S Firestein (gfirestein{at}
          1. UCSD School of Medicine, United States


            Objectives: The IKK-related kinase IKK∊ regulates type I interferon expression and responses as well as pro-inflammatory mediator production. We examined the role of IKK∊ in arthritis and its ability to enhance the therapeutic response to systemic IFNβ therapy in passive murine K/BxN arthritis.

            Methods: IKK∊-/-, IFNα/βR-/- and wild type mice were given K/BxN serum and treated with poly(I:C), IFNβ, or normal saline. Clinical response and histologic scores were assessed. Gene expression in the paws was measured by quantitative PCR. Serum IL-1Ra and IL-10 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 TLR3 ligand, p(I:C), were co-administered at the onset of the model, but not in established disease. Mice deficient in IFNα/βR had an accelerated course of arthritis, and did not respond to poly(I:C). IKK∊ 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 IKK∊ null mice. Articular chemokine gene expression was reduced in the IKK∊-/- mice with arthritis and sIL-1Ra mRNA was significantly increased. Serum levels of IL-1Ra were increased in low dose IFNβ-treated IKK∊-/- mice.

            Conclusions: Subtherapeutic doses of IFNβ enhance the anti-inflammatory effects of IKK∊ deficiency, possibly by increasing production of IL-1Ra and unmasking the anti-chemokine effects. Combination therapy with low dose IFNβ and an IKK∊ inhibitor might improve efficacy of either agent alone and offers a novel approach to RA.

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