IκB kinase β inhibitor, IMD-0354, prevents allergic asthma in a mouse model through inhibition of CD4(+) effector T cell responses in the lung-draining mediastinal lymph nodes

Eur J Pharmacol. 2016 Mar 15;775:78-85. doi: 10.1016/j.ejphar.2016.02.023. Epub 2016 Feb 9.

Abstract

IκB kinase (IKK) is important for nuclear factor (NF)-κB activation under inflammatory conditions. It has been demonstrated that IMD-0354, i.e. a selective inhibitor of IKKβ, inhibited allergic inflammation in a mouse model of ovalbumin (OVA)-induced asthma. The present study attempts to shed light on the involvement of CD4(+) effector (Teff) and regulatory (Treg) T cells in the anti-asthmatic action of IMD-0354. The animals were divided into three groups: vehicle treated, PBS-sensitized/challenged mice (PBS group); vehicle treated, OVA-sensitized/challenged mice (OVA group); and IMD-0354-treated, OVA-sensitized/challenged mice. The analyzed parameters included the absolute counts of Treg cells (Foxp3(+)CD25(+)CD4(+)), activated Teff cells (Foxp3(-)CD25(+)CD4(+)) and resting T cells (CD25(-)CD4(+)) in the mediastinal lymph nodes (MLNs), lungs and peripheral blood. Moreover, lung histopathology was performed to evaluate lung inflammation. It was found that the absolute number of cells in all studied subsets was considerably increased in the MLNs and lungs of mice from OVA group as compared to PBS group. All of these effects were fully prevented by treatment with IMD-0354. Histopathological examination showed that treatment with IMD-0354 protected the lungs from OVA-induced allergic airway inflammation. Our results indicate that IMD-0354 exerts anti-asthmatic action, at least partially, by blocking the activation and clonal expansion of CD4(+) Teff cells in the MLNs, which, consequently, prevents infiltration of the lungs with activated CD4(+) Teff cells. The beneficial effects of IMD-0354 in a mouse model of asthma are not mediated through increased recruitment of Treg cells into the MLNs and lungs and/or local generation of inducible Treg cells.

Keywords: Asthma; CD4(+) T cells; Lungs; MLNs; NF-κB; Treg cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allergens
  • Animals
  • Anti-Asthmatic Agents / pharmacology*
  • Anti-Asthmatic Agents / therapeutic use
  • Asthma / drug therapy*
  • Asthma / immunology
  • Benzamides / pharmacology*
  • Benzamides / therapeutic use
  • CD4-Positive T-Lymphocytes / drug effects*
  • CD4-Positive T-Lymphocytes / immunology
  • Disease Models, Animal
  • I-kappa B Kinase / antagonists & inhibitors*
  • Lung / drug effects
  • Lung / immunology
  • Lymph Nodes / drug effects
  • Lymph Nodes / immunology
  • Mice, Inbred BALB C
  • Ovalbumin

Substances

  • Allergens
  • Anti-Asthmatic Agents
  • Benzamides
  • N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide
  • Ovalbumin
  • I-kappa B Kinase