Received for publication February 2, 2006.
Revised April 24, 2006.
Accepted for publication May 8, 2006.

Validation of the anti-inflammatory properties of small molecule IKK2 inhibitors by comparison to adenoviral-mediated delivery of dominant negative IKK1 and IKK2 in human airways smooth muscle

Abstract

Asthma and chronic obstructive pulmonary disease (COPD) are characterized by chronic airways inflammation. However, because COPD patients and certain asthmatics show little or no therapeutic benefit from existing corticosteroid therapies there is an urgent need for novel anti-inflammatory strategies. The transcription factor NF-B is central to inflammation and is necessary for the expression of numerous inflammatory genes. Pro-inflammatory cytokines, including IL-1 and TNF, activate the IB kinase (IKK) complex to promote degradation of inhibitory IB proteins and activate NF-B. This pathway and, in particular the main IB kinase, IKK2, are now considered prime targets for novel anti-inflammatory drugs. We have therefore used adenoviral over-expression to demonstrate NF-B- and IKK2-dependence of key inflammatory genes, including ICAM-1, COX-2, IL-6, IL-8, GM-CSF, RANTES, MCP-1, GRO, NAP-2 and ENA78 in primary human airways smooth muscle cells. As this cell type is central to the pathogenesis of airway inflammatory diseases, these data predict a beneficial effect of IKK2 inhibition. These validated outputs were therefore used to evaluate the novel IKK inhibitors, PS-1145 and ML120B, on IL-1 and TNF-induced expression and this was compared with the corticosteroid dexamethasone. As observed above, ICAM-1, IL-6, IL-8, GM-CSF, RANTES, MCP-1, GRO, NAP-2 and ENA78 expression was reduced by the IKK inhibitors. Furthermore, this inhibition was either as effective, or for ICAM-1, MCP-1, GRO and NAP-2, more effective, than a maximally effective concentration of dexamethasone. We therefore suggest that IKK inhibitors may be of considerable benefit in inflammatory airways diseases, particularly in COPD or severe asthma, where corticosteroids are ineffective.

Key words: Interleukins, Tumor necrosis factor, NFkappaB, Regulation of gene expression, Regulation - transcriptional

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