The IKKβ Subunit of IκB Kinase (IKK) is Essential for Nuclear Factor κB Activation and Prevention of Apoptosis

Abstract

The IκB kinase (IKK) complex is composed of three subunits, IKKα, IKKβ, and IKKγ (NEMO). While IKKα and IKKβ are highly similar catalytic subunits, both capable of IκB phosphorylation in vitro, IKKγ is a regulatory subunit. Previous biochemical and genetic analyses have indicated that despite their similar structures and in vitro kinase activities, IKKα and IKKβ have distinct functions. Surprisingly, disruption of the Ikkα locus did not abolish activation of IKK by proinflammatory stimuli and resulted in only a small decrease in nuclear factor (NF)-κB activation. Now we describe the pathophysiological consequence of disruption of the Ikkβ locus. IKKβ-deficient mice die at mid-gestation from uncontrolled liver apoptosis, a phenotype that is remarkably similar to that of mice deficient in both the RelA (p65) and NF-κB1 (p50/p105) subunits of NF-κB. Accordingly, IKKβ-deficient cells are defective in activation of IKK and NF-κB in response to either tumor necrosis factor α or interleukin 1. Thus IKKβ, but not IKKα, plays the major role in IKK activation and induction of NF-κB activity. In the absence of IKKβ, IKKα is unresponsive to IKK activators.

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.…”

“…However, because NF-B is involved in normal immune and homeostatic processes, such as the prevention of apoptosis in certain tissues (e.g., liver) (20)(21)(22), its prolonged inhibition may have hazards and is unlikely to be a direct therapeutic target. 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).…”

“…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.…”

Specificity of insulin signalling in human skeletal muscle as revealed by small interfering RNA

“…IKKβ, but not IKKα, plays a major role in nuclear factor κB (NF-κB) activation and activity in response to proinflammatory cytokines such as TNF-α [57]. In type 2 diabetic patients [58] or lipid-infused healthy volunteers [59], increased IκB/NF-κB pathway activity is associated with skeletal muscle insulin resistance.…”

Activation of the NF-κB pathway by the leukemogenic TEL-Jak2 and TEL-Abl fusion proteins leads to the accumulation of antiapoptotic IAP proteins and involves IKKα

“…The IL-3-independent Ba/F3 cell line stably expressing the TEL-Jak2 and TEL-Abl fusion proteins have been reported (Constantino Rosa Santos et al, 2001). The murine embryonic fibroblasts (MEF) IKKg/NEMO À/À and wt cell lines were obtained from A Israel's laboratory (Institut Pasteur, Paris) and the IKKa À/À and IKKb À/À MEF (Li et al, 1999) cells were obtained from V Baud (CNRS, UPR 9079, Villejuif, France). MEFs were maintained in Dubelcco's Modified Eagle's Medium (Gibco-BRL) supplemented with 10% fetal calf serum, 2 mM L-glutamine, 100 units/ml penicillin and 100 mg/ml streptomycin.…”