Severe Liver Degeneration in Mice Lacking the IκB Kinase 2 Gene

TLDR

Phosphorylation of IκB proteins, essential for NF‑κB activation, requires the IKK complex comprising IKK1 and IKK2, with IKK1 associating with the NF‑κB essential modulator. IKK2‑deficient mice exhibit lethal embryonic liver apoptosis that can be rescued by TNFR1 deletion, and their embryonic fibroblasts show diminished TNF‑α/IL‑1α‑induced NF‑κB activity with increased apoptosis, confirming that IKK2 is indispensable for development and cannot be replaced by IKK1.

Abstract

Phosphorylation of inhibitor of kappa B (IkappaB) proteins is an important step in the activation of the transcription nuclear factor kappa B (NF-kappaB) and requires two IkappaB kinases, IKK1 (IKKalpha) and IKK2 (IKKbeta). Mice that are devoid of the IKK2 gene had extensive liver damage from apoptosis and died as embryos, but these mice could be rescued by the inactivation of the gene encoding tumor necrosis factor receptor 1. Mouse embryonic fibroblast cells that were isolated from IKK2-/- embryos showed a marked reduction in tumor necrosis factor-alpha (TNF-alpha)- and interleukin-1alpha-induced NF-kappaB activity and an enhanced apoptosis in response to TNF-alpha. IKK1 associated with NF-kappaB essential modulator (IKKgamma/IKKAP1), another component of the IKK complex. These results show that IKK2 is essential for mouse development and cannot be substituted with IKK1.