Antiallergic and anti-inflammatory effects of a novel I kappaB kinase beta inhibitor, IMD-0354, in a mouse model of allergic inflammation.

Abstract

BACKGROUND:

Nuclear factor (NF)-kappaB is a transcription factor known to regulate allergy-associated cytokine and chemokine production related to the induction of inflammation. I kappaB kinase beta (IKK beta), which is responsible for activation of the NF-kappaB 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.

• Authors: Akemi Sugita, Hirohisa Ogawa, Masahiko Azuma, Susumu Muto, Akifumi Honjo, Hiroaki Yanagawa, Yasuhiko Nishioka, Kenji Tani, Akiko Itai, Saburo Sone
• Journal: International archives of allergy and immunology (Int Arch Allergy Immunol) Vol. 148 Issue 3 Pg. 186-98 ( 2009) ISSN: 1423-0097 [Electronic] Switzerland
• PMID: 18849610 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2008 S. Karger AG, Basel.

Chemical References

• Anti-Allergic Agents
• Anti-Inflammatory Agents
• Benzamides
• Chemokines
• Cytokines
• Immunoglobulin E
• N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide
• Ovalbumin
• I-kappa B Kinase

Topics

• Airway Resistance (drug effects)
• Animals
• Anti-Allergic Agents (pharmacology, therapeutic use)
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Benzamides (pharmacology, therapeutic use)
• Body Weight (drug effects)
• Bronchoalveolar Lavage Fluid (chemistry, cytology)
• Cell Count
• Chemokines (analysis, metabolism)
• Cytokines (analysis, metabolism)
• Disease Models, Animal
• Eosinophils (cytology)
• Female
• I-kappa B Kinase (antagonists & inhibitors, metabolism)
• Immunoglobulin E (blood, immunology)
• Lung (drug effects, metabolism, pathology, physiopathology)
• Lymphocytes (cytology)
• Macrophages (cytology)
• Mice
• Mice, Inbred BALB C
• Ovalbumin (administration & dosage, immunology)
• Respiratory Hypersensitivity (drug therapy, pathology, physiopathology)