Dataset Information

Let-7 miRNAs Modulate the Activation of NF-?B by Targeting TNFAIP3 and Are Involved in the Pathogenesis of Lupus Nephritis.

ABSTRACT: TNFAIP3 is a ubiquitin-editing enzyme that negatively regulates multiple NF-?B signaling pathways and dysregulation of TNFAIP3 is related to systemic lupus erythematosus (SLE). Although there exists evidence indicating that microRNAs (miRNAs) modulate the expression of TNFAIP3, whether and how miRNAs regulate TNFAIP3 and contribute to lupus nephritis (LN) is still not well understood. In this study, we screened eleven selected miRNAs that potentially regulated TNFAIP3 expression by dual luciferase assay and found that Let-7 miRNAs repressed TNFAIP3 expression by targeting the 3'UTR of TNFAIP3 mRNA. Overexpression of Let-7 miRNAs led to increased phosphorylation and sustained degradation of I?B? and enhanced phosphorylation of p65 following TNF? stimulation and promoted SeV-induced production of cytokines in HEK293T cells. In addition, the expression of Let-7 miRNAs was significantly up-regulated, and TNFAIP3 level was remarkably down-regulated in samples from LN patients compared control samples. Our findings have uncovered Let-7-TNFAIP3-NF-?B pathway that is involved in LN and thus provided a potential target for therapeutic intervention.

SUBMITTER: Liu J

PROVIDER: S-EPMC4482407 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Let-7 miRNAs Modulate the Activation of NF-κB by Targeting TNFAIP3 and Are Involved in the Pathogenesis of Lupus Nephritis.

Liu Jun J Zhu Lin L Xie Guang-liang GL Bao Jing-fang JF Yu Qing Q

PloS one 20150625 6

TNFAIP3 is a ubiquitin-editing enzyme that negatively regulates multiple NF-κB signaling pathways and dysregulation of TNFAIP3 is related to systemic lupus erythematosus (SLE). Although there exists evidence indicating that microRNAs (miRNAs) modulate the expression of TNFAIP3, whether and how miRNAs regulate TNFAIP3 and contribute to lupus nephritis (LN) is still not well understood. In this study, we screened eleven selected miRNAs that potentially regulated TNFAIP3 expression by dual lucifera ...[more]

PMID: 26110642

Similar Datasets

Project description:BACKGROUND:Systemic lupus erythematosus (SLE) is an autoimmune inflammatory rheumatic disease. SLE susceptibility is affected by multiple genetic elements, environmental factors, and their interactions. We aimed in this study to statistically and functionally characterize a gene-gene interaction (epistasis) recently documented to affect SLE risk. METHODS:Two single-nucleotide polymorphisms, rs2230926 in TNFAIP3 (A20) gene and rs131654 in UBE2L3 (UBCH7) gene, were genotyped in all 3525 Korean participants, and their SLE risk association and epistasis were statistically analyzed by calculating odds ratio (OR), 95% confidence interval (CI), and P values in genotype comparisons between 1318 SLE patients and 2207 healthy controls. Furthermore, their effects on gene functions were assessed by comparatively examining separate and combined effects of TNFAIP3 and UBE2L3 knockdowns on NF-?B transcription factor activity in human cells. RESULTS:SLE susceptibility is associated with TNFAIP3 rs2230926 (OR?=?1.9, 95% CI 1.6-2.4, P =?8.6?×?10-11) and UBE2L3 rs131654 (OR?=?1.2, 95% CI 1.1-1.4, P =?1.1?×?10-4) in a Korean population of this study. Their risk-associated alleles synergistically elevate SLE susceptibility in both multivariate logistic regression analysis (ORinteraction =?1.6, P =?0.0028) and genotype-stratified analysis (ORinteraction =?2.4), confirming the synergistic TNFAIP3-UBE2L3 interaction in SLE risk. Additionally, the SLE-susceptible alleles confer decreased TNFAIP3 expression (P =?1.1?×?10-6, n =?610) and increased UBE2L3 expression (P =?9.5?×?10-11, n =?475), respectively, in B cell analysis of the International HapMap Project individuals with adjustment for ethnicity. Furthermore, when compared with TNFAIP3 non-knockdown and UBE2L3 knockdown in human HeLa cells, TNFAIP3 knockdown and UBE2L3 non-knockdown synergistically increase three cytokines, CCL2, CXCL8 (IL8), and IL6, all regulated by NF-?B in the human TNFR signaling pathway. CONCLUSIONS:A synergistic interaction between TNFAIP3 and UBE2L3 genes is observed in SLE risk, as being evident in comparison of genotype distributions between SLE patients and controls. Additionally, the synergistic gene-gene interaction is functionally validated, as TNFAIP3 reduction and UBE2L3 augment exert synergism in activation of NF-?B and subsequent induction of inflammatory cytokines. Accordingly, SLE inflammation and risk could be synergistically alleviated by TNFAIP3 upregulation and UBE2L3 downregulation.

Dataset Information

Let-7 miRNAs Modulate the Activation of NF-?B by Targeting TNFAIP3 and Are Involved in the Pathogenesis of Lupus Nephritis.

Publications

Let-7 miRNAs Modulate the Activation of NF-κB by Targeting TNFAIP3 and Are Involved in the Pathogenesis of Lupus Nephritis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets