Article Text

other Versions

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

            Abstract

            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.

            Statistics from Altmetric.com

            Request permissions

            If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

            Linked Articles