Overexpression of microRNA-21 is associated with elevated pro-inflammatory cytokines in dominant-negative TGF-β receptor type II mouse

Ando, Yumiko; Yang, Guo Xiang; Kenny, Thomas P.; Kawata, Kazuhito; Zhang, Weici; Huang, Wenting; Leung, Patrick S.C.; Lian, Zhe Xiong; Okazaki, Kazuichi; Ansari, Aftab A.; He, Xiao; Invernizzi, Pietro; Ridgway, William M.; Lu, Qianjin; Gershwin, M. Eric

doi:10.1016/j.jaut.2012.12.013

Cited by 94 publications

(70 citation statements)

References 48 publications

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“…These results suggest that the overexpression of miR-21 could decrease the expression of TGF-β1 mRNA, which further down-regulates the frequency of circulating Treg cells and foxp3 mRNA levels [39]. In turn, the decrease in Treg cell frequency and the down-regulation of foxp3 result in less TGF-β1 secretion, suggesting an inhibition of the anti-inflammatory effect of Treg cells.…”

Section: Expression Levels Of Mir-21 Foxp3 Tgf-β1 and Smad7 In Pbmcmentioning

confidence: 85%

MicroRNA-21 Negatively Regulates Treg Cells Through a TGF-β1/Smad-Independent Pathway in Patients with Coronary Heart Disease

Fan

et al. 2015

Cell Physiol Biochem

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Background: CD4+CD25+FoxP3+ regulatory T cells (Treg cells) play a protective role against the development and progression of the inflammatory disease atherosclerosis (AS). MicroRNA-21 (miR-21) is expressed in Treg cells and is up-regulated in the context of AS and other inflammatory diseases. Aims: This study aimed to determine the role of miR-21 in Treg cell regulation and gene expression during the development of AS in patients with coronary heart disease (CHD). Methods and Results: MiR-21 expression in peripheral blood mononuclear cells (PBMCs) was significantly up-regulated in patients with CHD (acute myocardial infarction (AMI) group, n=24; unstable angina (UA) group, n=21; stable angina (SA) group, n=24) compared with patients with chest pain syndrome (CPS, n=27), and miR-21 expression showed an increasing trend from SA to UA to AMI patients. Moreover, flow cytometry analysis indicated that the frequencies of circulating Treg cells decreased in a manner proportionate opposite with the level of miR-21. Quantitative real-time PCR (qRT-PCR) revealed a decrease in mRNA expression of forkhead box P3 (foxp3), transforming cell growth factor beta 1(TGF-β1) and smad7 (a known target gene of miR-21). ELISA analysis revealed a decrease in TGF-β1 secreted into the plasma. In addition, we transfected PBMCs with a miRNA negative control (NS-m), a miR-21 mimic (miR-21-m), a miRNA inhibitor negative control (NS-i), or a miR-21 inhibitor(miR-21-i). Up-regulation of miR-21 decreased the frequency of circulating Treg cells, decreased the expression levels of foxp3, TGF-β1 and smad7, and decreased the amount of TGF-β1 secreted into the plasma. Consistent with these observations, miR-21 down-regulation increased the frequency of circulating Treg cells, increased the expression of foxp3, TGF-β1 and smad7, and increased the amount of TGF-β1 secreted into the plasma. Conclusions: Because the smad7 expression pattern was similar to that of TGF-β, our study suggests that miR-21 can negatively regulate the frequency of circulating Treg cells through a TGF-β1/smad-independent signaling pathway in PBMCs.

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Section: Expression Levels Of Mir-21 Foxp3 Tgf-β1 and Smad7 In Pbmcmentioning

confidence: 85%

MicroRNA-21 Negatively Regulates Treg Cells Through a TGF-β1/Smad-Independent Pathway in Patients with Coronary Heart Disease

Fan

et al. 2015

Cell Physiol Biochem

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“…Nevertheless, it has been reported that suppression of miR-21 causes a reduction in the pro-inflammatory cytokine TNF-α and monocyte chemoattractant protein-1 in a mouse model of type 2 diabetes [38]. Another study revealed that overexpression of miR-21 resulted in up-regulation of TNF-α and interferon-γ in B6 T cells [39]. Therefore, these results indicate that miR-21 may play different roles in various types of cells and tissues in response to a variety of stimuli.…”

Section: Discussionmentioning

confidence: 99%

MiR-21 Regulates TNF-α-Induced CD40 Expression via the SIRT1-NF-κB Pathway in Renal Inner Medullary Collecting Duct Cells

Lin

Geng

Zhao

et al. 2017

Cell Physiol Biochem

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Background/Aims: Recent studies have indicated that microRNA-21 (miR-21) is involved in the inflammatory response in relation to renal disease. Sirtuin1 (SIRT1) exerts renoprotective properties by counteracting inflammation. The activation of CD40 triggers inflammation that participates in renal inflammation and injury. The relationship between miR-21, SIRT1 and CD40, however, remains elusive. Methods: Immunohistochemistry, small-interfering RNA (siRNA) transfection, quantitative real-time PCR and western blotting were applied to assess the morphological, functional and molecular mechanisms in primary cultured renal inner medullary collecting duct (IMCD) cells. Results: TNF-α induced miR-21, CD40 and acetylated-NF-κBp65 (Ac-p65) expressions and reduced SIRT1 expression in IMCD cells. miR-21 mimics increased SIRT1 expression and attenuated Ac-p65 and CD40 expressions in TNF-α-induced IMCD cells, and the corresponding changes were observed with a miR-21 inhibitor. SIRT1 overexpression or activation by SRT1720 diminished TNF-α-induced CD40 and Ac-p65 expressions, which was reversed by SIRT1 siRNA or the inhibitors Ex527 and sirtinol and augmented by pretreatment with NF-κB siRNA. Further study found that the inhibitory effect of miR-21 on Ac-p65 and CD40 expressions was impeded by pretreatment with SIRT1 siRNA. Conclusion: The present study indicates that miR-21 inhibits TNF-α-induced CD40 expression in IMCD cells via the SIRT1-NF-κB signalling pathway, which provides new insight in understanding the anti-inflammatory effect of miR-21.

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“…These opposing actions are analogous to pressing the gas pedal while stepping on the brake; however, it takes days for the repressive miR-21 to build up in a cell before blocking translation (29)(30)(31). This provides a plausible mechanism for suppression of T-cell activation to limit the immune response.…”

Section: Predictions Of Transcription Factor Locations In Promoter Rementioning

confidence: 99%

Spaceflight alters expression of microRNA during T‐cell activation

Hughes‐Fulford

Chang²,

Martinez

et al. 2015

The FASEB Journal

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Altered immune function has been demonstrated in astronauts during spaceflights dating back to Apollo and Skylab; this could be a major barrier to long-term space exploration. We tested the hypothesis that spaceflight causes changes in microRNA (miRNA) expression. Human leukocytes were stimulated with mitogens on board the International Space Station using an onboard normal gravity control. Bioinformatics showed that miR-21 was significantly up-regulated 2-fold during early T-cell activation in normal gravity, and gene expression was suppressed under microgravity. This was confirmed using quantitative realtime PCR (n = 4). This is the first report that spaceflight regulates miRNA expression. Global microarray analysis showed significant (P < 0.05) suppression of 85 genes under microgravity conditions compared to normal gravity samples. EGR3, FASLG, BTG2, SPRY2, and TAGAP are biologically confirmed targets and are co-up-regulated with miR-21. These genes share common promoter regions with pre-mir-21; as the miR-21 matures and accumulates, it most likely will inhibit translation of its target genes and limit the immune response. These data suggest that gravity regulates T-cell activation not only by transcription promotion but also by blocking translation via noncoding RNA mechanisms. Moreover, this study suggests that T-cell activation itself may induce a sequence of gene expressions that is self-limited by miR-21.-HughesFulford, M., Chang, T. T., Martinez, E. M., Li, C.-F. Spaceflight alters expression of microRNA during T-cell activation. FASEB J. 29, 4893-4900 (2015). www.fasebj.org

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Overexpression of microRNA-21 is associated with elevated pro-inflammatory cytokines in dominant-negative TGF-β receptor type II mouse

Cited by 94 publications

References 48 publications

MicroRNA-21 Negatively Regulates Treg Cells Through a TGF-β1/Smad-Independent Pathway in Patients with Coronary Heart Disease

MicroRNA-21 Negatively Regulates Treg Cells Through a TGF-β1/Smad-Independent Pathway in Patients with Coronary Heart Disease

MiR-21 Regulates TNF-α-Induced CD40 Expression via the SIRT1-NF-κB Pathway in Renal Inner Medullary Collecting Duct Cells

Spaceflight alters expression of microRNA during T‐cell activation

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