ps1145 and Pulmonary-Disease--Chronic-Obstructive

Nuclear factor-kappaB (NFkappaB) is an inducible transcription factor that plays a central role in the regulation of many immune and inflammatory responses. While NFkappaB is required for cell survival and immunity, abnormal expression and/or activation of NFkappaB leads to the development of many pathological states, especially those involved in chronic and acute inflammation. Many different signal transduction pathways, originating from a wide variety of cellular stresses and stimuli, converge on a single target; the NFkappaB/IkappaB complex and its activating kinase (inhibitor of kappaB kinase, IKK). Here, we review some of the major NFkappaB activating pathways, their role in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD), and their potential as targets in the treatment of asthma and COPD.

Topics: Anti-Inflammatory Agents; Asthma; Heterocyclic Compounds, 3-Ring; Humans; I-kappa B Kinase; Imidazoles; NF-kappa B; Protein Serine-Threonine Kinases; Pulmonary Disease, Chronic Obstructive; Pyridines; Quinoxalines

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)-kappaB, 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 kappaB kinase (IKK) inhibitors. In A549 cells, interleukin (IL)-1beta and tumor necrosis factor (TNF) alpha increased phosphorylation of IkappaBalpha, and this was followed by loss of IkappaBalpha, induction of NF-kappaB DNA binding, and the induction of NF-kappaB-dependent transcription. These events were repressed by the IKK-selective inhibitors, PS-1145 [N-(6-chloro-9H-beta-carbolin-8-ly) nicotinamide] and ML120B [N-(6-chloro-7-methoxy-9H-beta-carbolin-8-yl)-2-methyl-nicotinamide]. Inhibition of NF-kappaB-dependent transcription was concentration-dependent and correlated with loss of intercellular adhesion molecule (ICAM)-1 expression. Similarly, IL-1beta- and TNFalpha-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 alpha, and monocyte chemotactic protein-1 (MCP-1) was also significantly repressed. Likewise, PS-1145 and ML120B profoundly reduced NF-kappaB-dependent transcription induced by IL-1beta and TNFalpha 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-kappaB-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.

Topics: Carbolines; Cells, Cultured; Cytokines; Epithelial Cells; Gene Expression Regulation; Heterocyclic Compounds, 3-Ring; Humans; I-kappa B Kinase; Interleukin-1beta; Interleukin-6; Interleukin-8; Lung; NF-kappa B; Niacinamide; Protein Kinase Inhibitors; Pulmonary Disease, Chronic Obstructive; Pyridines; Transcription, Genetic; Tumor Necrosis Factor-alpha

Asthma and chronic obstructive pulmonary disease (COPD) are characterized by chronic airway inflammation. However, because patients with COPD and certain patients with asthma show little or no therapeutic benefit from existing corticosteroid therapies, there is an urgent need for novel anti-inflammatory strategies. The transcription factor nuclear factor-kappaB (NF-kappaB) is central to inflammation and is necessary for the expression of numerous inflammatory genes. Proinflammatory cytokines, including interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha, activate the IkappaB kinase complex (IKK) to promote the degradation of inhibitory IkappaB proteins and activate NF-kappaB. This pathway and, in particular, the main IkappaB kinase, IKK2, are now considered prime targets for novel anti-inflammatory drugs. Therefore, we have used adenoviral overexpression to demonstrate NF-kappaB and IKK2 dependence of key inflammatory genes, including intercellular adhesion molecule (ICAM)-1, cyclooxygenase-2, IL-6, IL-8, granulocyte macrophage-colony-stimulating factor (GM-CSF), regulated on activation normal T cell expressed and secreted (RANTES), monocyte chemotactic protein-1 (MCP-1), growth-regulated oncogene-alpha (GROalpha), neutrophil-activating protein-2 (NAP-2), and epithelial neutrophil activating peptide 78 (ENA-78) in primary human airways smooth muscle cells. Because 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 N-(6-chloro-9H-beta-carbolin-8-yl) nicotinamide (PS-1145) and N-(6-chloro-7-methoxy-9H-beta-carbolin-8-yl)-2-methyl-nicotinamide (ML120B) on IL-1beta and TNFalpha-induced expression, and this was compared with the corticosteroid dexamethasone. As observed above, ICAM-1, IL-6, IL-8, GM-CSF, RANTES, MCP-1, GROalpha, NAP-2, and ENA-78 expression was reduced by the IKK inhibitors. Furthermore, this inhibition was either as effective, or for ICAM-1, MCP-1, GROalpha, 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, in which corticosteroids are ineffective.

Topics: Adenoviridae; Anti-Inflammatory Agents; Bronchi; Cell Survival; Cells, Cultured; Dexamethasone; Gene Expression; Heterocyclic Compounds, 3-Ring; Humans; I-kappa B Kinase; Intercellular Adhesion Molecule-1; Muscle, Smooth; NF-kappa B; Protein Kinase Inhibitors; Pulmonary Disease, Chronic Obstructive; Pyridines; Tumor Necrosis Factor-alpha