Antiallergic and Anti-Inflammatory Effects of a Novel IκB Kinase β Inhibitor, IMD-0354, in a Mouse Model of Allergic Inflammation

• Published in: International archives of allergy and immunology Vol. 148; no. 3; pp. 186 - 198
• Main Authors: Sugita, Akemi, Ogawa, Hirohisa, Azuma, Masahiko, Muto, Susumu, Honjo, Akifumi, Yanagawa, Hiroaki, Nishioka, Yasuhiko, Tani, Kenji, Itai, Akiko, Sone, Saburo
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland Karger 01.02.2009
• Subjects: Biological and medical sciences; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Medical sciences; Original Paper; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; IMD-0354; Bronchial asthma; Allergic inflammation; IĸB kinase β inhibitor; Immunoglobulin E; Nuclear factor-ĸB; Th1/Th2 balance; Airway hyperresponsiveness; Allergy; Animal model; Hyperreactivity; IgE; Th1 lymphocyte; Respiratory system; Antiallergic; Respiratory tract; Immunology; T-Lymphocyte; Bronchus disease; Th2 lymphocyte; Obstructive pulmonary disease; Transcription factor NFκB; IκB kinase β inhibitor; Lung disease; Immunopathology; Respiratory disease; Rodentia; Antiinflammatory agent; Bronchus; Inflammation; Nuclear factor-κB; Asthma; Vertebrata; Mammalia; Mouse
• ISSN: 1018-2438; 1423-0097
• DOI: 10.1159/000161579

Background: Nuclear factor (NF)-κB is a transcription factor known to regulate allergy-associated cytokine and chemokine production related to the induction of inflammation. IκB kinase β (IKKβ), which is responsible for activation of the NF-κB pathway, may be an ideal molecular target to inhibit this process. IMD-0354 [N-(3,5-bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxy-benzamide] is an attractive novel IKKβ inhibitor that prevents the production of inflammatory cytokines in various diseases, although it is not known if IMD-0354 is effective against allergic inflammation. This study aimed to elucidate the antiallergic effects of a newly synthesized IKKβ inhibitor, IMD-0354, in a mouse model of allergic inflammation. Methods: We generated ovalbumin (OVA)-sensitized mice which were then challenged with OVA. IMD-0354 was administered intraperitoneally to therapeutic groups. Lung histopathology and the concentrations of cytokines and chemokines in bronchoalveolar lavage fluid (BALF) and supernatants of lung homogenates were determined. Results: Administration of IMD-0354 ameliorated airway hyperresponsiveness and reduced the numbers of bronchial eosinophils and mucus-producing cells in OVA-sensitized mice. The total numbers of cells and eosinophils in BALF were also reduced by treatment with IMD-0354. Treatment with IMD-0354 inhibited the production of Th2 cytokines such as interleukin (IL)-5 and IL-13 and eotaxin in the airways and/or lungs of OVA-sensitized mice, but it did not affect the restoration of Th1 cytokines such as IL-12 and interferon-γ under the same experimental conditions. IgE production was also inhibited by IMD-0354. Conclusion: A specific IKKβ inhibitor, IMD-0354, improved allergic airway inflammation and hyperresponsiveness in mice. IMD-0354 may have therapeutic potential for bronchial asthma.