Abstract
Inhibitor of κB (IκB) β (IκBβ) represents one of the major primary regulators of NF-κB in mammals. In contrast to the defined regulatory interplay between NF-κB and IκBα, much less is known about the biological function of IκBβ. To elucidate the physiological role of IκBβ in NF-κB signaling in vivo, we generated IκBβ-deficient mice. These animals proved to be highly refractory to LPS-induced lethality, accompanied by a strong reduction in sepsis-associated cytokine production. In response to LPS, IκBβ is recruited to the IL-1β promoter forming a complex with the NF-κB subunits RelA/c-Rel required for IL-1β transcription. Further transcriptome analysis of LPS-stimulated wild-type and IκBβ-deficient BM-derived macrophages revealed several other genes with known regulatory functions in innate immunity arguing that a subset of NF-κB target genes is under control of IκBβ. Collectively, these findings provide an essential proinflammatory role for IκBβ in vivo, and establish a critical function for IκBβ as a transcriptional coactivator under inflammatory conditions.