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Published on: January 22, 2019
Let-7a Inhibits T-Cell Proliferation and IFN-γ Secretion by Down-Regulating STAT3 Expression in Patients with
Xiao-Ping Hu1, Qian Xie2, Chao-Feng Chen1
1Department of Dermatology, Peking University Shenzhen Hospital, Shenzhen, China.
Objective:
This study aimed to explore the effects of STAT3 targeting by let-7a on T-cell proliferation and IFN-γ secretion in psoriasis.
Methods:
From January 2013 to January 2015, 40 patients with psoriasis (psoriasis group) and 38 volunteers undergoing plastic surgery (control group) were enrolled in this study. Pearson correlation analysis was performed to evaluate the correlation between let-7a and STAT3 expression. T-cells were isolated and subjected to different transfection methods. A dual luciferase reporter assay was carried out to confirm STAT3 as a target gene of let-7a. Let-7a, STAT3 and IFN-γ mRNA expression was detected by quantitative real-time fluorescent polymerase chain reaction (qRT-PCR), and pSTAT3 protein levels were determined by Western blot. T-cell proliferation was evaluated with a cell counting kit-8 (CCK-8) assay.
Results:
The level of STAT3 mRNA and pSTAT3 was higher, but let-7a expression was lower in the psoriasis group than the control group. Pearson correlation analysis indicated that STAT3 expression was negatively correlated with let-7a expression. T-cells transfected with inhibitors exhibited greater IFN-γ mRNA expression and T-cell proliferation than transfected T-cells and T-cells transfected with a non-sense sequence, while T-cells transfected with let-7a mimics exhibited lower IFN-γ mRNA expression and T-cell proliferation than transfected T-cells and T-cells transfected with a non-sense sequence. This suggested that siRNA-STAT3 could reverse the increase in IFN-y mRNA expression and T-cell proliferation induced by let-7a inhibitors.
Conclusion:
Our results demonstrated that let-7a inhibits T-cell proliferation and IFN-γ secretion by down-regulating STAT3 in psoriasis.
Insights
In psoriasis, low levels of let-7a correlate with increased STAT3 signaling, leading to higher T-cell proliferation and IFN-γ secretion. Targeting STAT3 with let-7a offers a potential therapeutic strategy.
Area of Science:
- Immunology
- Molecular Biology
- Dermatology
Background:
- Psoriasis is a chronic inflammatory skin disease characterized by aberrant immune cell activity.
- Signal transducer and activator of transcription 3 (STAT3) signaling is implicated in the pathogenesis of psoriasis.
- MicroRNAs, such as let-7a, are emerging as key regulators of gene expression in inflammatory conditions.
Purpose of the Study:
- To investigate the regulatory role of let-7a in targeting STAT3 within the context of T-cell responses in psoriasis.
- To determine the impact of let-7a and STAT3 interaction on T-cell proliferation and interferon-gamma (IFN-γ) secretion.
Main Methods:
- Comparative analysis of let-7a and STAT3 expression in psoriasis patients versus healthy controls.
- In vitro studies involving T-cell isolation and transfection with let-7a mimics, inhibitors, or siRNA targeting STAT3.
- Quantitative real-time PCR (qRT-PCR) for gene expression analysis (let-7a, STAT3, IFN-γ) and Western blot for pSTAT3 protein levels.
- Cell Counting Kit-8 (CCK-8) assay to assess T-cell proliferation.
Main Results:
- Patients with psoriasis exhibited lower let-7a expression and higher STAT3 mRNA and pSTAT3 protein levels compared to controls.
- A significant negative correlation was observed between STAT3 and let-7a expression.
- Manipulation of let-7a levels directly affected T-cell proliferation and IFN-γ secretion, with let-7a inhibition promoting these responses and let-7a mimics suppressing them. STAT3 inhibition reversed these effects.
Conclusions:
- Let-7a acts as a negative regulator of STAT3 in the context of psoriasis.
- Down-regulation of STAT3 by let-7a effectively inhibits T-cell proliferation and IFN-γ secretion, key drivers of psoriasis pathogenesis.
- These findings highlight the let-7a/STAT3 axis as a potential therapeutic target for psoriasis treatment.
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