Antiallergic and Anti-Inflammatory Effects of a Novel I kappa B Kinase beta Inhibitor, IMD-0354, in a Mouse Model of Allergic Inflammation

作者：Sugita Akemi; Ogawa Hirohisa; Azuma Masahiko; Muto Susumu; Honjo Akifumi; Yanagawa Hiroaki; Nishioka Yasuhiko; Tani Kenji; Itai Akiko; Sone Saburo^*

来源：International Archives of Allergy and Immunology, 2009, 148(3): 186-198.

DOI：10.1159/000161579

• Nuclear factor-kappa B
• IMD-0354
• I kappa B kinase beta inhibitor
• Allergic inflammation
• Airway hyperresponsiveness
• Th1/Th2 balance
• Immunoglobulin E
• Bronchial asthma

Background: Nuclear factor (NF)-kappa B is a transcription factor known to regulate allergy-associated cytokine and chemokine production related to the induction of inflammation. I kappa B kinase beta (IKK beta), which is responsible for activation of the NF-kappa B 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 IKK beta 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 IKK beta 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-gamma under the same experimental conditions. IgE production was also inhibited by IMD-0354. Conclusion: A specific IKK beta inhibitor, IMD-0354, improved allergic airway inflammation and hyperresponsiveness in mice. IMD-0354 may have therapeutic potential for bronchial asthma.

• 出版日期2009
• 单位河北医科大学