Synergistic benefit in inflammatory arthritis by targeting IKK and IFN

¹ University of California San Diego, United States
² University of California, San Diego, United States
³ UCSD School of Medicine, United States

^* To whom correspondence should be addressed. E-mail: mcorr{at}ucsd.edu.

Accepted 9 July 2008

	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 IFN therapy in passive murine K/BxN arthritis.

Methods: IKK^-/-, IFN/R^-/- and wild type mice were given K/BxN serum and treated with poly(I:C), IFN, 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 IFN/R 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 IFN 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 IFN-treated IKK^-/- mice.

Conclusions: Subtherapeutic doses of IFN 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 IFN and an IKK inhibitor might improve efficacy of either agent alone and offers a novel approach to RA.