IκB kinase β inhibitor, BMS-345541, suppresses the dendritic cell response in a murine model of allergic airway inflammation

Abstract

Abstract Pharmacological IκB kinase (IKK) inhibition could be an effective therapeutic strategy for the prevention and treatment of allergic asthma. Recently, we have demonstrated that a selective inhibitor of IKKβ prevented allergic asthma in a mouse model through inhibition of CD4+ effector T cell responses in the lung-draining mediastinal lymph nodes (MLNs). However, the precise mechanism responsible for this effect was not been fully elucidated. The migration of dendritic cells (DCs) from the lungs to the regional lymph nodes is necessary for the development of allergic airway inflammation (AAI). The study attempts to shed light on the involvement of DCs in the anti-asthmatic action of BMS-345541 (BMS), i.e. a selective inhibitor of IKKβ. We studied the effect of a 7-day treatment with BMS on the development of AAI and the absolute count of CD11chighCD11b+CD103− (CD11b+) and CD11chighCD11b−CD103+(CD103+) DCs in the MLNs and lungs of OVA-sensitized/challenged mice. The absolute count of CD11b+ and CD103+ DCs was increased in the MLNs of untreated OVA-immunized mice. Moreover, the absolute number of CD11b+, but not CD103+, DCs was increased in the lungs of these mice. BMS reduced, but did not fully prevent, the OVA-induced increase in the count of migratory CD11b+ DCs in the MLNs. In turn, administration of this agent prevented the OVA-induced increase in absolute counts of CD103+ DCs in the MLNs and CD11b+ DCs in the lungs. Treatment with BMS protected the lungs from OVA-induced AAI. These results strongly suggest that one of the mechanisms, and probably a key one, underlying the anti-asthmatic action of IKKβ inhibitors is the suppression of the formation of inflammatory DCs at the inflammatory site and their accumulation in the draining lymph nodes.