Received for publication October 3, 2005.
Revised March 1, 2006.
Accepted for publication March 2, 2006.

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

Abstract

NF-B 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-B pathway activation in a steroid-sensitive animal model of LPS-driven airway inflammation. Interestingly, 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-B-dependent or - independent by determining the impact of an IB kinase-2 (IKK-2) inhibitor, TPCA- 1. In the LPS model TPCA-1 blocked the increase in NF-B:DNA binding, a marker of NF-B pathway activation. This inhibition was associated with a reduction in inflammatory mediator release (TNF/IL-l/MMP-9) and lung inflammatory cell burden (neutrophilia/eosinophilia); data paralleled with a steroid and in human cell based assays. In the elastase-driven inflammation model, in which our group has previously failed to measure an increase in NF- B:DNA binding, neither TPCA-1, nor the steroid, impacted on mediator release (IL-1/MMP- 9) or cellular burden (neutrophilia/lymphomononuclear cells). This is the first study examining the effect of an IKK-2 inhibitor in well validated models which mimic aspects of the inflammatory lesion evident in diseases such as COPD. In conclusion we have demonstrated that animal models with similar profiles of airway inflammation can be IKK-2 inhibitor/steroid sensitive or insensitive. If both profiles of inflammation exist in the clinic, then this finding is extremely exciting and may lead to greater understanding of disease pathology and the discovery of novel anti- inflammatory targets.

Key words: NFkappaB, Regulation of gene expression, Leukocytes/Mast cells

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