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 0007-1188

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Abstract

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
ISSN:	0007-1188
Date:	May 2005
Volume:	145
Number:	1
Number of Pages:	9
Page Range:	pp. 114-122
Publication Status:	Published
URI:	http://wrap.warwick.ac.uk/id/eprint/7067

Data sourced from Thomson Reuters' Web of Knowledge

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