Inhibitor of nuclear factor ?B kinase ? is a key regulator of synovial inflammation

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Abstract
Objective Inhibitor of nuclear factor κB kinase β (IκB kinase β, or IKKβ) has emerged as a key regulator of the transcription factor nuclear factor κB (NF-κB). Since IKKβ could have both pro- and antiinflammatory activity, we examined whether its constitutive activation was sufficient to cause a chronic inflammatory disease such as rheumatoid arthritis. Methods Normal Lewis rats were evaluated for paw swelling by plethysmometry and histologic assessment after intraarticular injection of an adenoviral construct encoding the IKKβ wild-type gene (Ad.IKKβ-wt); controls received an adenoviral construct encoding green fluorescent protein (Ad.GFP). The rats were killed after 7 days. Additionally, rats were killed 48 hours after intraarticular injection of Ad.IKKβ-wt or Ad.GFP for studies of IKK activity and NF-κB binding. For studies of the effects of inhibition of IKKβ activity, Lewis rats were immunized with Mycobacterium tuberculosis in mineral oil. The ankle joints were injected on day 12 with an adenoviral construct encoding IKKβ K→M (dominant negative, IKKβ-dn) or Ad.GFP. We evaluated paw swelling and NF-κB expression on day 25. Results Intraarticular gene transfer of IKKβ-wt into the joints of normal rats resulted in significant paw swelling and histologic evidence of synovial inflammation. Increased IKK activity was detectable in the IKKβ-wt–injected ankle joints, coincident with enhanced NF-κB DNA binding activity. Intraarticular gene transfer of IKKβ-dn significantly ameliorated the severity of adjuvant arthritis, accompanied by a significant decrease in NF-κB DNA expression in the joints of Ad.IKKβ-dn–treated animals. Conclusion IKKβ plays a key role in rodent synovial inflammation. Intraarticular gene therapy to inhibit IKKβ activity represents an attractive strategy for the treatment of chronic arthritis.