Iκ-B kinase-2 inhibitor blocks inflammation in human airway smooth muscle and a rat model of asthma

Rationale: Nuclear factor (NF)-kappa B is a transcription factor known to regulate the expression of many inflammatory genes, including cytokines, chemokines, and adhesion molecules. NF-kappa B is held inactive in the cytoplasm, bound to I-kappa B. The removal Of I-kappa B, via the actions of inhibitor of kappa B (I-kappa B) kinase-2 (IKK-2), allows NF-kappa B to enter the nucleus. Objectives: To determine the impact of inhibiting IKK-2 on in vitro and in vivo models of airway inflammation. Methods: The effect of inhibiting IKK-2 was assessed in stimulated, cultured, primary human airway smooth muscle cells and an antigen-driven rat model of lung inflammation. Measurements: The release of cytokines from cultured cells and inflammatory cytokine expression and cellular burden in the lung were determined. Main Results: Two structurally distinct molecules and dominant negative technology demonstrated that inhibition of IKK-2 activity completely blocked cytokine release from cultured cells, whereas the two glucocorticoid comparators had limited impact on granulocyte colony-stimulating factor, interleukin 8, and eotaxin release. In addition, in an in vivo antigen-driven model of airway inflammation, the IKK-2 inhibitor blocked NF-kappa B nuclear translocation, which was associated with a reduction in inflammatory cytokine gene and protein expression, airway eosinophilia, and late asthmatic reaction, similar in magnitude to that obtained with budesonide. Conclusion: This study demonstrates that inhibiting IKK-2 results in a general reduction of the inflammatory response in vitro and in vivo. Compounds of this class could have therapeutic utility in the treatment of asthma and may, in certain respects, possess a beneficial efficacy profile compared with that of a steroid.