IκBβ acts to both inhibit and activate gene expression at different stages of the inflammatory response

The activation of pro-inflammatory gene programs by nuclear factor-κB (NF-κB) is primarily regulated through cytoplasmic sequestration of NF-κB by the inhibitor of κB (IκB) family of proteins1. IκBβ, a major IκB isoform, can sequester NF-κB in the cytoplasm2, although its biological role remains unclear. While cells lacking IκBβ have been reported3,4, in vivo studies have been limited and suggested redundancy between IκBα and IκBβ5. Like IκBα, IκBβ is also inducibly degraded, however upon stimulation by LPS, IκBβ is degraded slowly and resynthesized as a hypophosphorylated form that can be detected in the nucleus6–11. The crystal structure of IκBβ bound to p65 suggested this complex might bind DNA12. In vitro, hypophosphorylated IκBβ can bind DNA with p65 and cRel, and the DNA-bound NF-κB:IκBβ complexes are resistant to IκBα, suggesting hypophosphorylated, nuclear IκBβ may prolong the expression of certain genes9–11. We now report that in vivo IκBβ serves to both inhibit and facilitate the inflammatory response. IκBβ degradation releases NF-κB dimers which upregulate pro-inflammatory target genes such as tumor necrosis factor-α (TNFα). Surprisingly absence of IκBβ results in a dramatic reduction of TNFα in response to lipopolysaccharide (LPS) even though activation of NF-κB is normal. The inhibition of TNFα mRNA expression correlates with the absence of nuclear, hypophosphorylated-IκBβ bound to p65:c-Rel heterodimers at a specific κB site on the TNFα promoter. Therefore IκBβ acts through p65:c-Rel dimers to maintain prolonged expression of TNFα. As a result, IκBβ(−/−) mice are resistant to LPS-induced septic shock and collagen-induced arthritis. Blocking IκBβ might be a promising new strategy for selectively inhibiting the chronic phase of TNFα production during the inflammatory response.