Dataset Information

NF-?B-DICER-miRs Axis Regulates TNF-? Expression in Responses to Endotoxin Stress.

ABSTRACT: Unbalanced tumor necrosis factor (TNF)-? production is associated with pathogenesis of a variety of human diseases. However, the molecular pathways maintaining TNF-? homeostasis remain elusive. Here, we report that NF-?B/p65-DICER-miRs axis negatively regulates TNF-? production. We demonstrated that NF-?B bound to DICER promoter and transcriptionally regulated DICER expression. In addition, the NF-?B/DICER signaling suppresses TNF-? expression by generating mature forms of miR-125b and miR-130a which negatively regulate TNF-? mRNA. Furthermore, we showed that the hepatocyte-specific depletion of Dicer in mice resulted in TNF-? overproduction and sensitized the mice to endotoxin, which could be corrected by administration of miR-125b mimics. These data suggest that NF-?B/p65-DICER-miRs axis involved in maintaining of TNF-? homeostasis, and injection of miR-125b as a potential therapeutic method for septic shock.

SUBMITTER: Guan Y

PROVIDER: S-EPMC4582149 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

NF-κB-DICER-miRs Axis Regulates TNF-α Expression in Responses to Endotoxin Stress.

Guan Yi Y Yao Hailan H Wang Junfeng J Sun Kailai K Cao Liu L Wang Yizheng Y

International journal of biological sciences 20150909 11

Unbalanced tumor necrosis factor (TNF)-α production is associated with pathogenesis of a variety of human diseases. However, the molecular pathways maintaining TNF-α homeostasis remain elusive. Here, we report that NF-κB/p65-DICER-miRs axis negatively regulates TNF-α production. We demonstrated that NF-κB bound to DICER promoter and transcriptionally regulated DICER expression. In addition, the NF-κB/DICER signaling suppresses TNF-α expression by generating mature forms of miR-125b and miR-130a ...[more]

PMID: 26435691

Similar Datasets

Project description: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.

Dataset Information

NF-?B-DICER-miRs Axis Regulates TNF-? Expression in Responses to Endotoxin Stress.

Publications

NF-κB-DICER-miRs Axis Regulates TNF-α Expression in Responses to Endotoxin Stress.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets