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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Repression of Inflammatory Gene Expression in Human Pulmonary Epithelial Cells by Small-Molecule IB Kinase Inhibitors

Respiratory Research Group, Departments of Cell Biology and Anatomy, Physiology and Biophysics, and Medicine, University of Calgary, Calgary, Alberta, Canada (R.N., N.S.H., W.O., R.L., D.P.); and National Heart and Lung Institute, Imperial College London, London, United Kingdom (M.C.C., P.J.B.)

The airway epithelium is critical in the pathogenesis of chronic inflammatory diseases, such as asthma and chronic obstructive pulmonary disease, and, by expressing numerous inflammatory genes, plays a prominent role in disease exacerbations. Since inflammatory gene expression often involves the transcription factor nuclear factor (NF)-B, this signaling pathway represents a site for anti-inflammatory intervention. As the airway epithelium is targeted by inhaled therapeutic agents, for example corticosteroids, human A549 pulmonary cells and primary human bronchial epithelial (HBE) cells were selected to evaluate inhibitor of B kinase (IKK) inhibitors. In A549 cells, interleukin (IL)-1 and tumor necrosis factor (TNF) increased phosphorylation of IB, and this was followed by loss of IB, induction of NF-B DNA binding, and the induction of NF-B-dependent transcription. These events were repressed by the IKK-selective inhibitors, PS-1145 [N-(6-chloro-9H--carbolin-8-ly) nicotinamide] and ML120B [N-(6-chloro-7-methoxy-9H--carbolin-8-yl)-2-methyl-nicotinamide]. Inhibition of NF-B-dependent transcription was concentration-dependent and correlated with loss of intercellular adhesion molecule (ICAM)-1 expression. Similarly, IL-1- and TNF-induced expression of IL-6, IL-8, granulocyte macrophage-colony-stimulating factor (GM-CSF), regulated and activation normal T cell expressed and secreted (RANTES), growth-related oncogene , and monocyte chemotactic protein-1 (MCP-1) was also significantly repressed. Likewise, PS-1145 and ML120B profoundly reduced NF-B-dependent transcription induced by IL-1 and TNF in primary HBE cells. Parallel effects on ICAM-1 expression and a significant repression of IL-8 release were observed. In contrast, the corticosteroid, dexamethasone, was without effect on NF-B-dependent transcription or the expression of ICAM-1. The above data provide strong support for an anti-inflammatory effect of IKK2 inhibitors acting on the pulmonary epithelium and suggest that such compounds may prove beneficial in situations where traditional corticosteroid therapies prove inadequate.

Address correspondence to: Dr. Robert Newton, Department of Cell Biology and Anatomy, Respiratory Research Group, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada. E-mail: rnewton{at}ucalgary.ca

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