![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
B Kinase (IKK)-2 Inhibitors by Comparison with Adenoviral-Mediated Delivery of Dominant-Negative IKK1 and IKK2 in Human Airways Smooth Muscle
National Heart & Lung Institute, Imperial College London, London, United Kingdom (M.C.C., M.B.S., K.F.C., P.J.B.); Millennium Pharmaceuticals Inc., Cambridge, Massachusetts (B.J., S.-M.L., A.J.C.); Sanofi Aventis, Bridgewater, New Jersey (E.-B.H.); and Respiratory Research Group, Department of Cell Biology and Anatomy, University of Calgary, Calgary, Alberta, Canada (R.N.)
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-
B (NF-B) is central to inflammation and is necessary for the expression of numerous inflammatory genes. Proinflammatory cytokines, including interleukin (IL)-1
and tumor necrosis factor (TNF)-
, activate the IB kinase complex (IKK) to promote the 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. Therefore, we have used adenoviral overexpression to demonstrate NF-B 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- (GRO), 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--carbolin-8-yl) nicotinamide (PS-1145) and N-(6-chloro-7-methoxy-9H--carbolin-8-yl)-2-methyl-nicotinamide (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 ENA-78 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, in which corticosteroids are ineffective.
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, AB, Canada T2N 4N1. E-mail: rnewton{at}ucalgary.ca
This article has been cited by other articles:
|
|
 |
|
  M. Kaur, N. S. Holden, S. M. Wilson, M. B. Sukkar, K. F. Chung, P. J. Barnes, R. Newton, and M. A. Giembycz Effect of {beta}2-adrenoceptor agonists and other cAMP-elevating agents on inflammatory gene expression in human ASM cells: a role for protein kinase A Am J Physiol Lung Cell Mol Physiol, September 1, 2008; 295(3): L505 - L514. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Quante, Y. C. Ng, E. E. Ramsay, S. Henness, J. C. Allen, J. Parmentier, Q. Ge, and A. J. Ammit Corticosteroids Reduce IL-6 in ASM Cells via Up-Regulation of MKP-1 Am. J. Respir. Cell Mol. Biol., August 1, 2008; 39(2): 208 - 217. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. Catley, M. A. Birrell, E. L. Hardaker, J. de Alba, S. Farrow, S. Haj-Yahia, and M. G. Belvisi Estrogen Receptor {beta}: Expression Profile and Possible Anti-Inflammatory Role in Disease J. Pharmacol. Exp. Ther., July 1, 2008; 326(1): 83 - 88. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Tudhope, M. C. Catley, P. S. Fenwick, R. E. K. Russell, W. L. Rumsey, R. Newton, P. J. Barnes, and L. E. Donnelly The Role of I{kappa}B Kinase 2, but Not Activation of NF-{kappa}B, in the Release of CXCR3 Ligands from IFN-{gamma}-Stimulated Human Bronchial Epithelial Cells J. Immunol., November 1, 2007; 179(9): 6237 - 6245. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Duchene, F. Lecomte, S. Ahmed, C. Cayla, J. Pesquero, M. Bader, M. Perretti, and A. Ahluwalia A Novel Inflammatory Pathway Involved in Leukocyte Recruitment: Role for the Kinin B1 Receptor and the Chemokine CXCL5 J. Immunol., October 1, 2007; 179(7): 4849 - 4856. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Newton and N. S. Holden Separating Transrepression and Transactivation: A Distressing Divorce for the Glucocorticoid Receptor? Mol. Pharmacol., October 1, 2007; 72(4): 799 - 809. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Xie, M. B. Sukkar, R. Issa, N. M. Khorasani, and K. F. Chung Mechanisms of induction of airway smooth muscle hyperplasia by transforming growth factor-beta Am J Physiol Lung Cell Mol Physiol, July 1, 2007; 293(1): L245 - L253. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Newton, N. S. Holden, M. C. Catley, W. Oyelusi, R. Leigh, D. Proud, and P. J. Barnes Repression of Inflammatory Gene Expression in Human Pulmonary Epithelial Cells by Small-Molecule I{kappa}B Kinase Inhibitors J. Pharmacol. Exp. Ther., May 1, 2007; 321(2): 734 - 742. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
