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

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 −/− , IFNα~βR −/− 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 IFNα~βR 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.Type I interferons (IFNs) stimulate antiviral responses, but they paradoxically exhibit antiinflammatory properties. For instance, IFNβ reduces tumour necrosis factor (TNF)α, interleukin (IL)1β and IL6 production and enhances the release of anti-inflammatory mediators such as IL1 receptor antagonist (IL1Ra) and IL10. 1-3 Preclinical studies emphasising the antiinflammatory functions of IFNβ strongly supported its therapeutic potential in rheumatoid arthritis (RA Serum transfer and arthritis scoringArthritic adult K/BxN mice were bled and the sera were pooled. Groups of three to eight recipient mice were injected with 150 µl intraperitoneally on day 0. Some groups of mice also received IFNβ (Chemicon (3.6 × 10 7 IU/mg; or 1000 IU=28 ng)), normal saline (NS) or polyinosinic polycytidylic acid (poly(I:C); Sigma, St Louis, Missouri, USA) at the indicated doses intraperitoneally. Clinical arthritis scores were evaluated using a scale of 0-4 for each paw for a total score of 16. Ankle thickness was measured with a calliper (Manostat, Herisau, Switzerland) in mm. 22 HistologyWhole knee joint sections were stained with haematoxylin and eosin and safranin O (HistoTox, Boulder, Colorado, USA). Histopathological scoring was performed as previously described on a ...

The Prosurvival IKK-Related Kinase IKKϵ Integrates LPS and IL17A Signaling Cascades to Promote Wnt-Dependent Tumor Development in the Intestine

“…Few candidates such as IL1ra were upregulated in duodenum of b-cat c.a. /Ikke À/À mice, as similarly showed in a model of arthritis (48). As IL1ra antagonizes the function of IL1b, Ikke may potentiate IL1b signaling by limiting IL1ra expression.…”

Kinetic analysis of synovial signalling and gene expression in animal models of arthritis

“…IRF7 expression correlated with synovial RANTES, both of which are regulated by IKKε 42. As IKKε-deficient mice have a modest reduction in the severity of arthritis in passive K/BxN arthritis, IKKε might play a part in synovial innate immune responses 43. Alternatively, the mechanism might be due to an effect on central immunity with an indirect effect on joints.…”

Complex Regulation Pattern of IRF3 Activation Revealed by a Novel Dimerization Reporter System

“…Chronic IFN-I signaling is associated with hyperimmune activation and disease progression in persistent lymphocytic choriomeningitis virus infections (10,12). Additionally, it is well known that constitutive activation of the TBK1-IRF3 signaling axis leads to excess IFN-I production, which contributes to numerous human autoimmune diseases and autoinflammatory syndromes such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, inflammatory bowel disease, chronic obstructive pulmonary disease, and type II diabetes (13)(14)(15)(16). Several recent studies have also shown that the activity of the TBK1-IRF3 signaling axis is elevated in cancer cells and potentially promotes tumorigenesis (17)(18)(19).…”