Synergistic benefit in inflammatory arthritis by targeting IκB kinase ε and interferon β

Objectives: The I kappa B kinase (IKK)-related kinase IKK epsilon regulates type I interferon expression and responses as well as proinflammatory mediator production. We examined the role of IKKe in arthritis and its ability to enhance the therapeutic response to systemic interferon (IFN) beta therapy in passive murine K/BxN arthritis. Methods: IKK epsilon(-/-), IFN alpha(similar to)beta R(-/-) and wild type mice were given K/BxN serum and treated with polyinosinic polycytidylic acid (poly(I: C)), IFN beta, 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 IFN alpha(similar to)beta R had an accelerated course of arthritis, and did not respond to poly(I: C). IKKe null mice had a modest decrease in clinical arthritis compared with heterozygous mice. Low doses of IFNb that were ineffective in wild type mice significantly decreased clinical arthritis in IKKe null mice. Articular chemokine gene expression was reduced in the IKK epsilon(-/-) mice with arthritis and secreted IL1Ra (sIL1Ra) mRNA was significantly increased. Serum levels of IL1Ra were increased in low dose IFN beta-treated IKK epsilon(-/-) mice. Conclusions: Subtherapeutic doses of IFN beta enhance the anti-inflammatory effects of IKK epsilon deficiency, possibly by increasing production of IL1Ra and unmasking the antichemokine effects. Combination therapy with low dose IFN beta and an IKK epsilon inhibitor might improve efficacy of either agent alone and offers a novel approach to RA.