Abstract
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.
Highlights
Tumor necrosis factor (TNF) is a pleiotropic cytokine whose primary physiological function involves coordinating innate and adaptive immune responses [1]
Our study suggested that by insulating RelB heterodimers from the canonical NF-κB pathway, p100 enforced dynamical and gene controls of TNF signaling (Figure 9)
TNF engages the canonical pathway for activating RelA:p50 heterodimers, which induce the expression of specific immune response genes [2]
Summary
Tumor necrosis factor (TNF) is a pleiotropic cytokine whose primary physiological function involves coordinating innate and adaptive immune responses [1]. Brief TNF stimulation induces a transient RelA:p50 activity peak persisting in the nucleus for about an hour. Chronic TNF stimulation triggers an additional second wave of protracted RelA:p50 activity, which lasts in the nucleus for more than 8 h. This late RelA:p50 activity displays oscillatory behavior at single-cell resolution [7]. Regardless of the duration of TNF treatment, RelA:p50 induce rapid synthesis of the inhibitors of the canonical pathway, including IκBα, IκBε, and A20 [9, 10]. It is thought that RelA:p50 regulation by the canonical NF-κB pathway largely provides for distinct transcriptional outputs to brief and chronic TNF stimulations [14]. On the other hand, deregulated TNF signaling has been implicated in several human ailments, including inflammatory bowel disorders and neoplastic diseases [1]
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