Abstract
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 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 IκBα and enhanced phosphorylation of p65 following TNFα 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-κB pathway that is involved in LN and thus provided a potential target for therapeutic intervention.
Highlights
Lupus nephritis (LN) is a kind of kidney disorder caused by systemic lupus erythematosus (SLE), which is a highly complex autoimmune disease
To confirm that the expression of TNFAIP3 was repressed by miRNAs, we first suppressed the expression of AGO2, a core component of RNA induced silencing complex (RISC), by AGO2 specific siRNA in HEK293T cells and examined the expression of TNFAIP3
nuclear factor-κB (NF-κB) is a transcription factor critically involved in development, immunity, inflammation and tumorigenesis
Summary
Lupus nephritis (LN) is a kind of kidney disorder caused by systemic lupus erythematosus (SLE), which is a highly complex autoimmune disease. LN contributes to the major cause of morbidity and mortality in patients with SLE, affecting up to 70% of SLE patients [1]. Emerging evidence shows that a large number of cytokines and chemokines were involved in the pathogenesis of LN [3,4,5,6]. It has been well recognized that the transcription factor nuclear factor-κB (NF-κB) plays a critical role in regulating the expression of inflammatory cytokines and chemokines. Stimulation with inflammatory signals such as TNFα or LPS results in phosphorylation-dependent degradation of IκBα, whereas stimulation with a PLOS ONE | DOI:10.1371/journal.pone.0121256. Stimulation with inflammatory signals such as TNFα or LPS results in phosphorylation-dependent degradation of IκBα, whereas stimulation with a PLOS ONE | DOI:10.1371/journal.pone.0121256 June 25, 2015
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