Ikappa-B kinase-2 inhibitor blocks inflammation in human airway smooth muscle and a rat model of asthma.
BACKGROUND
Nuclear factor (NF)-kappaB is a transcription factor known to regulate the expression of many inflammatory genes, including cytokines, chemokines, and adhesion molecules. NF-kappaB is held inactive in the cytoplasm, bound to I-kappaB. The removal of I-kappaB, via the actions of inhibitor of kappaB (I-kappaB) kinase-2 (IKK-2), allows NF-kappaB to enter the nucleus.


OBJECTIVE
To determine the impact of inhibiting IKK-2 on in vitro and in vivo models of airway inflammation.


METHODS
The effect of inhibiting IKK-2 was assessed in stimulated, cultured, primary human airway smooth muscle cells and an antigen-driven rat model of lung inflammation.


METHODS
The release of cytokines from cultured cells and inflammatory cytokine expression and cellular burden in the lung were determined.


RESULTS
Two structurally distinct molecules and dominant negative technology demonstrated that inhibition of IKK-2 activity completely blocked cytokine release from cultured cells, whereas the two glucocorticoid comparators had limited impact on granulocyte colony-stimulating factor, interleukin 8, and eotaxin release. In addition, in an in vivo antigen-driven model of airway inflammation, the IKK-2 inhibitor blocked NF-kappaB nuclear translocation, which was associated with a reduction in inflammatory cytokine gene and protein expression, airway eosinophilia, and late asthmatic reaction, similar in magnitude to that obtained with budesonide.


CONCLUSIONS
This study demonstrates that inhibiting IKK-2 results in a general reduction of the inflammatory response in vitro and in vivo. Compounds of this class could have therapeutic utility in the treatment of asthma and may, in certain respects, possess a beneficial efficacy profile compared with that of a steroid.
Respiratory Pharmacology Group, National Heart and Lung Institute, Imperial College Faculty of Medicine, London, UK.
Mark A
MA
Birrell
Elizabeth
E
Hardaker
Sissie
S
Wong
Kerryn
K
McCluskie
Matthew
M
Catley
Jorge
J
De Alba
Robert
R
Newton
Saleem
S
Haj-Yahia
K Tao
KT
Pun
Clarissa J
CJ
Watts
Robert J
RJ
Shaw
Tony J
TJ
Savage
Maria G
MG
Belvisi
D000577:Amides / Q000276:immunology / Q000627:therapeutic use*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000276:immunology / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D019819:Budesonide / Q000276:immunology / Q000627:therapeutic use; D002478:Cells, Cultured / Q000187:drug effects / Q000276:immunology; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000276:immunology; D003907:Dexamethasone / Q000276:immunology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D016179:Granulocyte Colony-Stimulating Factor / Q000187:drug effects / Q000276:immunology; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000276:immunology; D007249:Inflammation; D016209:Interleukin-8 / Q000276:immunology; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000503:physiopathology; D016328:NF-kappa B / Q000187:drug effects / Q000276:immunology; D051381:Rats; D012137:Respiratory System / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000503:physiopathology; D013876:Thiophenes / Q000276:immunology / Q000627:therapeutic use*
D000577:Amides; D000893:Anti-Inflammatory Agents; C515456:CCL11 protein, human; C515458:Ccl11 protein, rat; D054413:Chemokine CCL11; D019742:Chemokines, CC; D016209:Interleukin-8; D016328:NF-kappa B; D013876:Thiophenes; D016179:Granulocyte Colony-Stimulating Factor; D019819:Budesonide; D003907:Dexamethasone; C499326:2-((aminocarbonyl)amino)-5-(4-fluorophenyl)-3-thiophenecarboxamide; D051550:I-kappa B Kinase