Validation of IKK beta as therapeutic target in airway inflammatory disease by adenoviral-mediated delivery of dominant-negative IKK beta to pulmonary epithelial cells
UNSPECIFIED. (2005) Validation of IKK beta as therapeutic target in airway inflammatory disease by adenoviral-mediated delivery of dominant-negative IKK beta to pulmonary epithelial cells. BRITISH JOURNAL OF PHARMACOLOGY, 145 (1). pp. 114-122. ISSN 0007-1188Full text not available from this repository.
1 Asthma is an inflammatory disease of the lungs and the transcription factor NF-κ 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-κ B activation are considered prime targets for novel anti-inflammatory therapies. The prevention of NF-κ B activity in mice, through the knockout of IKKβ or p65, causes fatal liver degeneration in utero making it difficult to determine the full implications of inhibiting NF-κ B activity in tissues physiologically relevant to human diseases.
2 This study used adenovirus delivery of a dominant inhibitor of NF-κ B(Iκ Bα&UDelta; N) and dominant-negative IKKα (IKKα(KM)) and IKKβ (IKKβ(KA)) to investigate the role of the individual IKKs in NF-κ B activation and inflammatory gene transcription by human pulmonary A549 cells.
3 Overexpression of IKKβ(KA) or IkBα&UDelta; N prevented NF-κ B-dependent transcription and DNA binding. IKKβ(KA) also prevented Iκ Bα kinase activity. Similarly, IKKβ(KA) and Iκ Bα&UDelta; N overexpression also inhibited IL-1β- and TNFα-dependent increases in ICAM-1, IL-8 and GMCSF in addition to IL-1β- mediated increases in cyclooxygenase-2 expression, whereas IKKα(KM) overexpression had little effect on these outputs.
4 IKKβ(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 IKKβ kinase activity since Iκ Bα&UDelta; N only induced PARP cleavage in TNFα-treated cells.
5 These results demonstrate that inhibition of IKKβ and NF-κ B suppresses inflammatory mediator production and reduces A549 cell viability. Thus, novel therapies that target IKKβ could have potent anti-inflammatory effects and may be beneficial in the treatment of certain cancers.
|Item Type:||Journal Article|
|Subjects:||R Medicine > RS Pharmacy and materia medica|
|Journal or Publication Title:||BRITISH JOURNAL OF PHARMACOLOGY|
|Publisher:||NATURE PUBLISHING GROUP|
|Official Date:||May 2005|
|Number of Pages:||9|
|Page Range:||pp. 114-122|
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