RELB

Abstract: The non-canonical NF-κB pathway is an important arm of NF-κB signaling that predominantly targets activation of the p52/RelB NF-κB complex. This pathway depends on the inducible processing of p100, a molecule functioning as both the precursor of p52 and a RelB-specific inhibitor. A central signaling component of the non-canonical pathway is NF-κB-inducing kinase (NIK), which integrates signals from a subset of TNF receptor family members and activates a downstream kinase, IκB kinase-α (IKKα), for triggering p100 phosphorylation and processing. A unique mechanism of NIK regulation is through its fate control: the basal level of NIK is kept low by a TRAF-cIAP destruction complex and signal-induced non-canonical NF-κB signaling involves NIK stabilization. Tight control of the fate of NIK is important, since deregulated NIK accumulation is associated with lymphoid malignancies.

Abstract: The noncanonical nuclear factor-κB (NF-κB) signaling pathway mediates activation of the p52/RelB NF-κB complex and, thereby, regulates specific immunological processes. This NF-κB pathway relies on the inducible processing of NF-κB2 precursor protein, p100, as opposed to the degradation of IκBα in the canonical NF-κB pathway. A central signaling component of the noncanonical NF-κB pathway is NF-κB-inducing kinase (NIK), which functions together with a downstream kinase, IKKα (inhibitor of NF-κB kinase α), to induce phosphorylation-dependent ubiquitination and processing of p100. Under normal conditions, NIK is targeted for continuous degradation by a tumor necrosis factor (TNF) receptor-associated factor-3 (TRAF3)-dependent E3 ubiquitin ligase. In response to signals mediated by a subset of TNF receptor superfamily members, NIK becomes stabilized as a result of TRAF3 degradation, leading to the activation of noncanonical NF-κB. This review discusses both the historical perspectives and the recent progress in the regulation and biological function of the noncanonical NF-κB pathway.

Abstract: Vascular endothelial growth factor (VEGF), produced by almost all tumor cells, affects the ability of hemopoietic progenitor cells (HPC) to differentiate into functional dendritic cells (DC) during the early stages of their maturation. In this study we demonstrate specific binding of VEGF to HPC. This binding was efficiently competed by placenta growth factor (PIGF), a ligand reportedly specific for the Flt-1 receptor. The number of binding sites for VEGF decreased during DC maturation in vitro associated with decreased levels of mRNA for Flt-1. VEGF significantly inhibited nuclear factor-kappa B (NF-kappa B)-dependent activation of reporter gene transcription during the first 24 h in culture. The presence of VEGF significantly decreased the specific DNA binding of NF-kappa B as early as 30 min after induction with TNF-alpha. This was followed on days 7 to 10 by decreases in the mRNA for RelB and c-Rel, two subunits of NF-kappa B. Blockade of NF-kappa B activity in HPC at early stages of differentiation with an adenovirus expressing a dominant I kappa B inhibitor of NF-kappa B reproduced the pattern of effects observed with VEGF. Thus, NF-kappa B plays an important role in maturation of HPCs to DC, and VEGF activation of the Flt-1 receptor is able to block the activation of NF-kappa B in this system. Blockade of NF-kappa B activation in HPCs by tumor-derived factors may therefore be a mechanism by which tumor cells can directly down-modulate the ability of the immune system to generate effective antitumor immune responses.

Abstract: In this commentary, we have suggested that the fibroblast should be considered a sentinel cell. This concept is based on the fibroblast's ability to function both as a structural element and as a vital immunoregulatory cell. In some tissues, these capabilities may be ascribable to subsets of fibroblasts, rather than to some of the general fibroblast populations. The pioneering research of Xia et al, as well as that of others, highlights the need to explore the importance of fibroblasts as playing critical roles in disease. Emerging concepts regarding tissue-specific fibroblasts and fibroblast heterogeneity need to be considered in studies of their biosynthetic capabilities. Of special importance is the recent insight that the NF kappa B/RelB family of transcription proteins have apparently different regulatory roles in fibroblasts and hematopoietic cells. Therefore, with regard to therapeutic strategies targeting molecules such as RelB, caution should be exercised as their interruption may have very different consequences in macrophages compared with fibroblasts. For example, inhibition of RelB in macrophages may well prevent enhanced chemokine expression, whereas in fibroblasts, a critical governor for preventing chemokine expression would be lost. Overall, this could lead to exacerbation of inflammation rather than to an attenuation of the process.