IκBβ is an essential co-activator for LPS-induced IL-1β transcription in vivo

Inhibitor of kappa B (I kappa B) beta (I kappa B beta) represents one of the major primary regulators of NF-kappa B in mammals. In contrast to the defined regulatory interplay between NF-kappa B and I kappa B alpha, much less is known about the biological function of I kappa B beta. To elucidate the physiological role of I kappa B beta in NF-kappa B signaling in vivo, we generated I kappa B beta-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, I kappa B beta is recruited to the IL-1 beta promoter forming a complex with the NF-kappa B subunits RelA/c-Rel required for IL-1 beta transcription. Further transcriptome analysis of LPS-stimulated wild-type and I kappa B beta-deficient BM-derived macrophages revealed several other genes with known regulatory functions in innate immunity arguing that a subset of NF-kappa B target genes is under control of I kappa B beta. Collectively, these findings provide an essential proinflammatory role for I kappa B beta in vivo, and establish a critical function for I kappa B beta as a transcriptional coactivator under inflammatory conditions.