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

Am J Respir Crit Care Med. 2005 Oct 15;172(8):962-71. doi: 10.1164/rccm.200412-1647OC. Epub 2005 Jul 7.


Rationale: Nuclear factor (NF)-kappaB is a transcription factor known to regulate the expression of many inflammatory genes, including cytokines, chemokines, and adhesion molecules. NF-kappaB is held inactive in the cytoplasm, bound to I-kappaB. The removal of I-kappaB, via the actions of inhibitor of kappaB (I-kappaB) kinase-2 (IKK-2), allows NF-kappaB 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-kappaB 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / immunology
  • Amides / therapeutic use*
  • Animals
  • Anti-Inflammatory Agents / immunology
  • Anti-Inflammatory Agents / therapeutic use
  • Asthma / drug therapy*
  • Asthma / immunology
  • Asthma / physiopathology
  • Budesonide / immunology
  • Budesonide / therapeutic use
  • Cells, Cultured / drug effects
  • Cells, Cultured / immunology
  • Chemokine CCL11
  • Chemokines, CC / immunology
  • Dexamethasone / immunology
  • Dexamethasone / therapeutic use
  • Disease Models, Animal*
  • Drug Evaluation, Preclinical
  • Gene Expression / drug effects
  • Gene Expression / immunology
  • Granulocyte Colony-Stimulating Factor / drug effects
  • Granulocyte Colony-Stimulating Factor / immunology
  • Humans
  • I-kappa B Kinase / antagonists & inhibitors*
  • I-kappa B Kinase / immunology
  • Inflammation
  • Interleukin-8 / immunology
  • Muscle, Smooth / cytology
  • Muscle, Smooth / drug effects*
  • Muscle, Smooth / immunology
  • Muscle, Smooth / physiopathology
  • NF-kappa B / drug effects
  • NF-kappa B / immunology
  • Rats
  • Respiratory System / cytology
  • Respiratory System / drug effects*
  • Respiratory System / immunology
  • Respiratory System / physiopathology
  • Thiophenes / immunology
  • Thiophenes / therapeutic use*


  • Amides
  • Anti-Inflammatory Agents
  • CCL11 protein, human
  • Ccl11 protein, rat
  • Chemokine CCL11
  • Chemokines, CC
  • Interleukin-8
  • NF-kappa B
  • Thiophenes
  • Granulocyte Colony-Stimulating Factor
  • Budesonide
  • Dexamethasone
  • 2-((aminocarbonyl)amino)-5-(4-fluorophenyl)-3-thiophenecarboxamide
  • I-kappa B Kinase