An epithelial Nfkb2 pathway exacerbates intestinal inflammation by supplementing latent RelA dimers to the canonical NF-κB module.

Aberrant inflammation, such as that associated with inflammatory bowel disease (IBD), is fueled by the inordinate activity of RelA/NF-κB factors. As such, the canonical NF-κB module mediates controlled nuclear activation of RelA dimers from the latent cytoplasmic complexes. What provokes pathological RelA activity in the colitogenic gut remains unclear. The noncanonical NF-κB pathway typically promotes immune organogenesis involving Nfkb2 gene products. Because NF-κB pathways are intertwined, we asked whether noncanonical signaling aggravated inflammatory RelA activity. Our investigation revealed frequent engagement of the noncanonical pathway in human IBD. In a mouse model of experimental colitis, we established that Nfkb2-mediated regulations escalated the RelA-driven proinflammatory gene response in intestinal epithelial cells, exacerbating the infiltration of inflammatory cells and colon pathologies. Our mechanistic studies clarified that cell-autonomous Nfkb2 signaling supplemented latent NF-κB dimers, leading to a hyperactive canonical RelA response in the inflamed colon. In sum, the regulation of latent NF-κB dimers appears to link noncanonical Nfkb2 signaling to RelA-driven inflammatory pathologies and may provide for therapeutic targets.

NCoR1: Putting the Brakes on the Dendritic Cell Immune Tolerance.

Understanding the mechanisms fine-tuning immunogenic versus tolerogenic balance in dendritic cells (DCs) is of high importance for therapeutic approaches. We found that NCoR1-mediated direct repression of the tolerogenic program in conventional DCs is essential for induction of an optimal immunogenic response. NCoR1 depletion upregulated a wide variety of tolerogenic genes in activated DCs, which consequently resulted in increased frequency of FoxP3+ regulatory T cells. Mechanistically, NCoR1 masks the PU.1-bound super-enhancers on major tolerogenic genes after DC activation that are subsequently bound by nuclear factor-κB. NCoR1 knockdown (KD) reduced RelA nuclear translocation and activity, whereas RelB was unaffected, providing activated DCs a tolerogenic advantage. Moreover, NCoR1DC-/- mice depicted enhanced Tregs in draining lymph nodes with increased disease burden upon bacterial and parasitic infections. Besides, adoptive transfer of activated NCoR1 KD DCs in infected animals showed a similar phenotype. Collectively, our results demonstrated NCoR1 as a promising target to control DC-mediated immune tolerance.

Immune Differentiation Regulator p100 Tunes NF-κB Responses to TNF.

Tumor necrosis factor (TNF) is a pleiotropic cytokine whose primary physiological function involves coordinating inflammatory and adaptive immune responses. However, uncontrolled TNF signaling causes aberrant inflammation and has been implicated in several human ailments. Therefore, an understanding of the molecular mechanisms underlying dynamical and gene controls of TNF signaling bear significance for human health. As such, TNF engages the canonical nuclear factor kappa B (NF-κB) pathway to activate RelA:p50 heterodimers, which induce expression of specific immune response genes. Brief and chronic TNF stimulation produces transient and long-lasting NF-κB activities, respectively. Negative feedback regulators of the canonical pathway, including IκBα, are thought to ensure transient RelA:p50 responses to short-lived TNF signals. The non-canonical NF-κB pathway mediates RelB activity during immune differentiation involving p100. We uncovered an unexpected role of p100 in TNF signaling. Brief TNF stimulation of p100-deficient cells triggered an additional late NF-κB activity consisting of RelB:p50 heterodimers, which modified the TNF-induced gene-expression program. In p100-deficient cells subjected to brief TNF stimulation, RelB:p50 not only sustained the expression of a subset of RelA-target immune response genes but also activated additional genes that were not normally induced by TNF in WT mouse embryonic fibroblasts (MEFs) and were related to immune differentiation and metabolic processes. Despite this RelB-mediated distinct gene control, however, RelA and RelB bound to mostly overlapping chromatin sites in p100-deficient cells. Repeated TNF pulses strengthened this RelB:p50 activity, which was supported by NF-κB-driven RelB synthesis. Finally, brief TNF stimulation elicited late-acting expressions of NF-κB target pro-survival genes in p100-deficient myeloma cells. In sum, our study suggests that the immune-differentiation regulator p100 enforces specificity of TNF signaling and that varied p100 levels may provide for modifying TNF responses in diverse physiological and pathological settings.

The NF-κB Activating Pathways in Multiple Myeloma.

Multiple myeloma(MM), an incurable plasma cell cancer, represents the second most prevalent hematological malignancy. Deregulated activity of the nuclear factor kappaB (NF-κB) family of transcription factors has been implicated in the pathogenesis of multiple myeloma. Tumor microenvironment-derived cytokines and cancer-associated genetic mutations signal through the canonical as well as the non-canonical arms to activate the NF-κB system in myeloma cells. In fact, frequent engagement of both the NF-κB pathways constitutes a distinguishing characteristic of myeloma. In turn, NF-κB signaling promotes proliferation, survival and drug-resistance of myeloma cells. In this review article, we catalog NF-κB activating genetic mutations and microenvironmental cues associated with multiple myeloma. We then describe how the individual canonical and non-canonical pathways transduce signals and contribute towards NF-κB -driven gene-expressions in healthy and malignant cells. Furthermore, we discuss signaling crosstalk between concomitantly triggered NF-κB pathways, and its plausible implication for anomalous NF-κB activation and NF-κB driven pro-survival gene-expressions in multiple myeloma. Finally, we propose that mechanistic understanding of NF-κB deregulations may provide for improved therapeutic and prognostic tools in multiple myeloma.