IKKβ Is Essential for Protecting T Cells from TNFα-Induced Apoptosis

Abstract

Transcription factor NF-kappaB, whose activation depends on the IKKbeta catalytic subunit of the IkappaB kinase, was assigned with both anti- and proapoptotic functions in T lymphocytes. To critically evaluate these functions, we transferred Ikkbeta-/- or wild-type (wt) fetal liver (FL) stem cells into lethally irradiated mice. Ikkbeta-/- radiation chimeras show thymic rudiments, aberrant lymphoid organs, and absence of T cells. T lymphopoiesis is rescued when Ikkbeta-/- stem cells are cotransferred with wt bone marrow, suggesting that IKKbeta may mediate its lymphopoietic function via extrinsic factors. However, almost normal development of Ikkbeta-/- T cells is observed upon removal of type 1 TNFalpha receptor, indicating that TNFalpha signaling accounts for the absence of Ikkbeta-/- T cells. Indeed, Ikkbeta-/- radiation chimeras exibit elevated circulating TNFalpha, and Ikkbeta-/- thymocytes display increased TNFalpha sensitivity.

NF-κB and the immune response

“…Targeted deletion of floxed-NEMO using cd4-promoter-driven Cre recombinase expression, or overexpression of kinase dead IKKb, results in loss of mature peripheral T cells (Schmidt-Supprian et al, 2004). These data strongly suggest that NF-kB activation is required for late stages of T-cell development; however, ikkb À/À, tnfr1 À/À double knockouts, ikkb À/À chimeras or cd4-Cre IKKb conditional knockouts are not defective in the production of naı¨ve T cells (Senftleben et al, 2001b;Schmidt-Supprian et al, 2004), suggesting a requirement for NEMO but not IKKb.…”

“…Likewise, B cells from p50 À/À mice do not respond efficiently to LPS, emphasizing the importance of p50-containing complexes, that is, p50/RelA, p50/ p50/BCL-3 and p50/c-Rel, in TLR signaling . As might be expected, TNFR/IKKb double knockouts show a more pronounced defect in innate responses owing to the more complete block in canonical NF-kB pathways, and succumb to infection more rapidly than rela À/À /tnfr1 À/À mice (Li et al, 1999a, b;Senftleben et al, 2001b). Furthermore, MEFs from nemo À/À mice do not exhibit NF-kB activation by LPS or IL-1 (Rudolph et al, 2000).…”

“…Interestingly, the activation of NF-kB in late B-cell maturation is the result of signaling by both canonical and non-canonical NF-kB pathways. Thus deficiency in NEMO, IKKa or IKKb decreases the numbers of mature B cells (Kaisho et al, 2001;Senftleben et al, 2001b;Pasparakis et al, 2002). Likewise, either p50/p52 or RelA/c-Rel double knockout progenitor cells are defective in their ability to mature beyond the transitional B-cell stage (Franzoso et al, 1997;Grossmann et al, 1999).…”

Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models

“…In addition to preventing TNFa-mediated hepatocyte apoptosis, RelA protects a number of other cell types including macrophages (Beg and Baltimore, 1996), B cells (Prendes et al, 2003) and T cells (Senftleben et al, 2001) from the TNF toxicity. However, this antiapoptotic role for RelA is not restricted to exposure to TNF, given that RelA also protects cells from cell death induced by double-stranded RNA, a TLR-9 ligand .…”

NF-κB Signaling Pathway, Inflammation and Colorectal Cancer

“…The activation events that modulate these pathways are mediated by a family of inhibitory kappa B kineses (IKKs); which consists of three core subunits, the catalytic subunits IKK and IKK and several copies of a regulatory subunit IKK. The first, known as the classical or canonical pathway depends on IKK, IKKβ activation, phosphorylates mainly IBα but also IBβ and IBε, which are present in the cytoplasm of unstimulated cells and undergo stimulus-induced degradation and resynthesis (20,21). Following stimulation with the various inflammatory stimuli, including certain members of tumor necrosis factor α (TNF-) cytokine family, IL-1, Toll-like receptor ligands (22)(23)(24)(25), the IB molecules are phosphorylated by the IKK complex, which leads to their degradation by the proteasome pathway (26).…”