Severe Liver Degeneration in Mice Lacking the IκB Kinase 2 Gene

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.

Heterogeneous requirement of IκB kinase 2 for inflammatory cytokine and matrix metalloproteinase production in rheumatoid arthritis: Implications for therapy

“…These studies did not examine endogenous NF-B-dependent promoters, nor did they look at cytokine gene expression induced by LPS (59,60). Moreover, IKK1dn could be equally effective as IKK2dn (60), a result that is inconsistent with evidence from mice deficient in these molecules (21,22,(25)(26)(27). In addition, our findings suggest significant differences in LPS signaling between macrophages and endothelial cells or fibroblasts.…”

“…Much more likely and more therapeutically attractive would be the selective inhibition of upstream molecules such as I B kinase 2 (IKK-2), a kinase previously shown to be essential for TNF␣-and IL-1-induced I B␣ degradation, NF-B activation, and cytokine expression (21)(22)(23)(24)(25)(26)(27)(28). One study recently demonstrated that IKK-2 is an important kinase required for TNF␣-or IL-1-induced NF-B activation and expression of IL-6, IL-8, intercellular adhesion molecule 1, and MMP-1 in passaged synoviocytes (29), although the significance of these observations in terms of the treatment of RA is not clear.…”

Glycogen synthase kinase-3β is a crucial mediator of signal-induced RelB degradation

“…The phenotype of GSK-3b-deficient mice (Hoeflich et al, 2000) is strikingly similar to the phenotype displayed by IKK-b-or RelA-deficient mice and characterized by embryonic death caused by increased apoptosis in the liver (Beg et al, 1995;Li et al, 1999). Moreover, mouse embryonic fibroblasts derived from these animals are more sensitive towards tumour necrosis factor-a-induced apoptosis than wildtype fibroblasts because of the inability of these mouse embryonic fibroblasts to induce NF-kB (Hoeflich et al, 2000).…”

FIP200, a key signaling node to coordinately regulate various cellular processes

“…The liver degeneration phenotype observed in FIP200 KO embryos is similar to the KO embryo phenotypes by deletion of several components in TNFα survival signaling pathways including Rel A, IKK-β, IKK-γ, GSK-3, MKK4, MKK7, or c-Jun, which are characterized by mid/late gestational lethality associated with increased apoptosis in liver [41][42][43][44][45][46][47]. Furthermore, FIP200 KO MEFs exhibit increased apoptosis upon TNFα treatment, which might be explained by the loss of FIP200 interaction with ASK1 and TRAF2, regulation of TRAF2-ASK1 interaction and ASK1 phosphorylation [12].…”