Validation of IKK beta as therapeutic target in airway inflammatory disease by adenoviral-mediated delivery of dominant-negative IKK beta to pulmonary epithelial cells

Br J Pharmacol. 2005 May;145(1):114-22. doi: 10.1038/sj.bjp.0706170.


Asthma is an inflammatory disease of the lungs and the transcription factor NF-kappa B regulates the production of numerous inflammatory mediators that may have a role in the pathogenesis of asthma. Hence, the signalling pathways leading to NF-kappa B activation are considered prime targets for novel anti-inflammatory therapies. The prevention of NF-kappa B activity in mice, through the knockout of IKK beta or p65, causes fatal liver degeneration in utero making it difficult to determine the full implications of inhibiting NF-kappaB activity in tissues physiologically relevant to human diseases. This study used adenovirus delivery of a dominant inhibitor of NF-kappaB (I kappa B alpha delta N) and dominant-negative IKK alpha (IKK alpha(KM)) and IKK beta (IKK beta(KA)) to investigate the role of the individual IKKs in NF-kappa B activation and inflammatory gene transcription by human pulmonary A549 cells. Overexpression of IKK beta(KA) or I kappa B alpha delta N prevented NF-kappa B-dependent transcription and DNA binding. IKK beta(KA) also prevented I kappa B alpha kinase activity. Similarly, IKK beta(KA) and I kappa B alpha delta N overexpression also inhibited IL-1beta- and TNF alpha-dependent increases in ICAM-1, IL-8 and GM-CSF in addition to IL-1beta-mediated increases in cyclooxygenase-2 expression, whereas IKK alpha(KM) overexpression had little effect on these outputs. IKK beta(KA) also reduced cell viability and induced caspase-3 and PARP cleavage regardless of the stimuli, indicating the induction of apoptosis. This effect seemed to be directly related to IKK beta kinase activity since I kappa B alpha delta N only induced PARP cleavage in TNF alpha-treated cells. These results demonstrate that inhibition of IKK beta and NF-kappa B suppresses inflammatory mediator production and reduces A549 cell viability. Thus, novel therapies that target IKK beta could have potent anti-inflammatory effects and may be beneficial in the treatment of certain cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae
  • Apoptosis
  • Asthma / metabolism
  • Cell Line
  • Epithelial Cells / metabolism
  • Gene Transfer Techniques
  • Genetic Vectors
  • Humans
  • I-kappa B Kinase
  • NF-kappa B / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology*
  • Respiratory Mucosa / cytology
  • Respiratory Mucosa / metabolism*
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / physiology


  • NF-kappa B
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human