The lymphotoxin-beta receptor (LTbetaR) plays critical roles in inflammation and lymphoid organogenesis through activation of NF-kappaB. In addition to activation of the classical NF-kappaB, ligation of this receptor induces the processing of the cytosolic NF-kappaB2/p100 precursor to yield the mature p52 subunit, followed by translocation of p52 to the nucleus. This activation of NF-kappaB2 requires NIK and IKKalpha, while NEMO/IKKgamma is dispensable for p100 processing. IKKbeta-dependent activation of canonical NF-kappaB is required for the expression but not processing of p100 and for the expression of proinflammatory molecules including VCAM-1, MIP-1beta, and MIP-2 in response to LTbetaR ligation. In contrast, IKKalpha controls the induction by LTbetaR ligation of chemokines and cytokines involved in lymphoid organogenesis, including SLC, BLC, ELC, SDF1, and BAFF.

IKK gamma/NEMO is the essential regulatory subunit of the I kappa B kinase (IKK), encoded by an X-linked gene in mice and humans. It is required for NF-kappa B activation and resistance to TNF-induced apoptosis. Female mice heterozygous for Ikk gamma/Nemo deficiency develop a unique dermatopathy characterized by keratinocyte hyperproliferation, skin inflammation, hyperkeratosis, and increased apoptosis. Although Ikk gamma+/- females eventually recover, Ikk gamma- males die in utero. These symptoms and inheritance pattern are very similar to those of incontinentia pigmenti (IP), a human genodermatosis, synthenic with the IKK gamma/NEMO locus. Indeed, biopsies and cells from IP patients exhibit defective IKK gamma/NEMO expression but normal expression of IKK catalytic subunits. This unique self-limiting disease, the first to be genetically linked to the IKK signaling pathway, is dependent on X-chromosome inactivation. We propose that the IKK gamma/NEMO-deficient cells trigger an inflammatory reaction that eventually leads to their death.

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The NF-B/Rel transcription factors participate in the activation of immune system regulatory genes and viral early genes including the human immunodeficiency virus type 1 long terminal repeat. NF-B/Rel proteins are coupled to inhibitory molecules, collectively termed IB, which are responsible for cytoplasmic retention of NF-B. Cell activation leads to the phosphorylation and degradation of IB␣, permitting NF-B/Rel translocation to the nucleus and target gene activation. To further characterize the signaling events that contribute to IB␣ phosphorylation, a kinase activity was isolated from Jurkat T cells that specifically interacted with IB␣ in an affinity chromatography step and phosphorylated IB␣ with high specificity in vitro. By using an in-gel kinase assay with recombinant IB␣ as substrate, two forms of the kinase (43 and 38 NF-B proteins are a family of pleiotropic transcription factors that regulate expression of numerous cytokines, and viral genes (for reviews, see references 27 and 48). In cells, NF-B is present in an inactive cytoplasmic form; localization of the p50-p65 heterodimeric form of NF-B to the cytoplasm is mediated by the inhibitory IB␣ protein that binds to and masks the nuclear localization signal of the p65 subunit of NF-B (5, 7). Activating agents, such as viruses, phorbol esters, cytokines, radical oxygen intermediates, and bacterial lipopolysaccharide, promote the dissociation of the cytosolic NF-B/IB complexes, in part by activating cellular kinases that phosphorylate IB (5-7, 22, 27, 48).The DNA-binding NF-B family members share a Rel homology domain that is responsible for DNA binding, nuclear localization, and protein dimerization. DNA-binding members of NF-B/Rel include p50 (NFKB1) (9, 23, 41), p65 (RelA) (52, 58), c-Rel (13, 24), p52 (NFKB2 or Lyt-10) (8, 51, 62), RelB (I-Rel) (59, 60), and dorsal (65). p50 and p52 are synthesized as precursors of p105 and p100, respectively, that are proteolytically processed to generate active DNA-binding p50 and p52 (8,9,23,41,51,62). Different NF-B dimers bind to variant NF-B sites (44) (consensus, 5Ј-GGGANNYYCC-3Ј) present in the promoter regions of many genes (reviewed in references 2 and 48).The intracellular localization and posttranslational activity of NF-B/Rel proteins are regulated by the ankyrin repeatcontaining IB proteins (IB␣, IB␥, Bcl-3, p105, and p100) (reviewed in references 5, 25, 28, and 39). Phosphorylation by activated cellular kinases and subsequent degradation of IB␣ appear to be critical regulatory steps in the control of NF-B activation. Recent studies demonstrated that mutation of either Ser-32 or Ser-36 blocked signal-induced IB␣ phosphorylation and degradation (10,11,69), and a truncated IB␣ that was missing 45 amino acids at the N terminus corrected radiation sensitivity in ataxia telangiectasia cells (37). Furthermore, IB␣ transcription is upregulated by NF-B, since the IB␣ promoter contains functional NF-B sites. Thus, an autoregulatory loop is established, and the ultimately increased IB␣ concentrations limit the...