IkappaB kinase-2-independent and -dependent inflammation in airway disease models: relevance of IKK-2 inhibition to the clinic

Molecular Pharmacology
Mark A BirrellMaria G Belvisi

Abstract

Nuclear factor kappaB (NF-kappaB) is a transcription factor believed to be central in the expression of numerous inflammatory genes and the pathogenesis of many respiratory diseases. We have previously demonstrated increased NF-kappaB pathway activation in a steroid-sensitive animal model of lipopolysaccharide (LPS)-driven airway inflammation. It is noteworthy that this phenomenon was not observed in a steroid-insensitive model of elastase-induced inflammation in the rat. The aim of this study was to gather further evidence to suggest that these similar profiles of neutrophilic inflammation can be NF-kappaB-dependent or -independent by determining the impact of an IkappaB kinase-2 (IKK-2) inhibitor, 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1). In the LPS model, TPCA-1 blocked the increase in NF-kappaB DNA binding, a marker of NF-kappaB pathway activation. This inhibition was associated with a reduction in inflammatory mediator release [tumor necrosis factor alpha (TNFalpha)/interleukin-1beta (IL-1beta)/matrix metalloproteinase-9 (MMP-9)] and lung inflammatory cell burden (neutrophilia/eosinophilia). These data were paralleled with a steroid and in human cell based assays. In the elastase-driven i...Continue Reading

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Citations

Feb 16, 2008·Nature Reviews. Immunology·Stephen T Holgate, Riccardo Polosa
Dec 17, 2008·Current Opinion in Pulmonary Medicine·Stephen T Holgate
Nov 5, 2008·The Journal of Clinical Investigation·Peter J Barnes
Jan 26, 2013·PloS One·Joseph M D RastrickMark A Birrell
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Jul 25, 2013·Pharmacology & Therapeutics·Steven BozinovskiRoss Vlahos
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Sep 5, 2008·The Journal of Immunology : Official Journal of the American Association of Immunologists·Mark A BirrellMaria G Belvisi
Oct 20, 2007·The Journal of Immunology : Official Journal of the American Association of Immunologists·Susan J TudhopeLouise E Donnelly

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