The role of IL-1β on IKKβ inhibitors induced neutrophilia (116.4)

Abstract Transcription factor NF-κB and its activating kinase IκB Kinase β (IKKβ) are critical for inflammation and immunity. Pharmacological inhibitors of IKKβ-NF-κB could be used for the treatment of inflammation. It was unexpected that IKKβ inhibitors (MLN120B) cause neutrophilia in mice but the mechanism remained unknown. IL-1β acted as a growth factor for myeloid progenitors and a survival factor for mature neutrophils. We tried to investigate the role of IL-1β on IKKβ inhibitors induced neutrophilia. Using conditional deletion of loxP-flanked Ikbkb alleles in myeloid cells in mice, we found severe neutrophilia after IKKβ deletion. Without any stimulus, Ikkβ-deleted mice produced more circulating IL-1β than age-matched wild-type mice. Isolated Ikkβ-deleted monocytes and macrophages secreted higher amounts of IL-1β than wild-type controls without stimulation. Treatment of wild-type mice with IKKβ inhibitors also led to neutrophilia within 8 days, which would be prevented by concomitant treatment with IL-1 receptor antagonis. Neutrophilia in mice after deletion of IKKβ seems IL-1β dependent. Excessive IL-1β signaling is responsible for the uncontrolled neutrophilia and inflammation in IKKβ-deleted mice. Enhanced IL-1β production represents a compensatory mechanism for maintaining immunity when NF-κB is inhibited and compensates for loss of NF-κB-dependent antibacterial immunity.