Inhibition of microRNA-155 relieves sepsis-induced liver injury through inactivating the JAK/STAT pathway

Lv, Xin; Zhang, Yucai; Cui, Yun; Ren, Yan; Li, Rui; Qi, Rong

doi:10.3892/mmr.2015.4188

Cited by 32 publications

(24 citation statements)

References 24 publications

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“…The Jak-STAT signaling pathway, T cell receptor signaling pathway, and natural killer cell-mediated pathway appeared in the downregulated gene set. The potential impact of these pathways in sepsis has already been stated in published studies [22][23][24][25][26]. The results showed that genes participating in immune and inflammatory responses have mixed differential expression patterns of both up-and downregulation.…”

Section: Discussionmentioning

confidence: 56%

Comprehensive Transcriptome Profiling of Peripheral Blood Mononuclear Cells from Patients with Sepsis

Wu¹,

Liang²,

Jiang³

et al. 2020

Int. J. Med. Sci.

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Background: Sepsis, as a clinical emergency, usually causes multiorgan dysfunction and can lead to high mortality. Establishment of specific and sensitive biomarkers for early diagnosis is critical to identify patients who would benefit from targeted therapy. In this study, we investigated this syndrome by analyzing the transcriptome of peripheral blood mononuclear cells (PBMCs) from patients with sepsis and identified sepsis-specific biomarkers. Methods: In this study, a total of 87 patients with sepsis and 40 healthy controls from a prospective multicenter cohort were enrolled. Samples from 44 subjects (24 patients with sepsis and 20 healthy controls) were sequenced and the remaining patients were included in the validation group. Using high-throughput sequencing, a gene expression profile of PBMCs from patients with sepsis was generated to elucidate the pathophysiology of sepsis and identify sepsis-specific biomarkers. Results: Principal component analysis (PCA) and unsupervised hierarchical cluster analysis showed that patients with sepsis separated from healthy controls. A total of 1639 differentially expressed genes (DEGs) were identified (|log2 fold change|>2, adjusted P value <0.05) between these two groups, with 1278 (78.0%) upregulated and 361 (22.0%) downregulated in patients with sepsis. Gene Ontology (GO) analysis of the upregulated DEGs identified 194 GO terms that were clustered into 27 groups, and analysis of the downregulated DEGs identified 20 GO terms that were clustered into 4 groups. Four unique genes were identified that could be predictive of patients with sepsis. External validation of the four genes using quantitative real-time polymerase chain reaction (qRT-PCR) was consistent with the results of mRNA sequencing, revealing their potential in sepsis diagnosis. Conclusions: The transcriptome characteristics of PBMCs, which were significantly altered in sepsis patients, provide new insights into sepsis pathogenesis. The four identified gene expression changes differentiated patients with sepsis from healthy subjects, which could serve as a convenient tool contributing to sepsis diagnosis.

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Section: Discussionmentioning

confidence: 56%

Comprehensive Transcriptome Profiling of Peripheral Blood Mononuclear Cells from Patients with Sepsis

Wu¹,

Liang²,

Jiang³

et al. 2020

Int. J. Med. Sci.

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“…It should be noted that inhibition of miR-155 improves outcomes in experimental peritonitis [ 38 , 39 ]. miRNAs have not yet been successfully used directly as a therapeutic modality in humans; however, some miRNAs are under investigation [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

IκK-16 decreases miRNA-155 expression and attenuates the human monocyte inflammatory response

et al. 2017

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Excessive inflammatory responses in the surgical patient may result in cellular hypo-responsiveness, which is associated with an increased risk of secondary infection and death. microRNAs (miRNAs), such as miR-155, are powerful regulators of inflammatory signalling pathways including nuclear factor κB (NFκB). Our objective was to determine the effect of IκK-16, a selective blocker of inhibitor of kappa-B kinase (IκK), on miRNA expression and the monocyte inflammatory response. In a model of endotoxin tolerance using primary human monocytes, impaired monocytes had decreased p65 expression with suppressed TNF-α and IL-10 production (P < 0.05). miR-155 and miR-138 levels were significantly upregulated at 17 h in the impaired monocyte (P < 0.05). Notably, IκK-16 decreased miR-155 expression with a corresponding dose-dependent decrease in TNF-α and IL-10 production (P < 0.05), and impaired monocyte function was associated with increased miR-155 and miR-138 expression. In the context of IκK-16 inhibition, miR-155 mimics increased TNF-α production, while miR-155 antagomirs decreased both TNF-α and IL-10 production. These data demonstrate that IκK-16 treatment attenuates the monocyte inflammatory response, which may occur through a miR-155-mediated mechanism, and that IκK-16 is a promising approach to limit the magnitude of an excessive innate inflammatory response to LPS.

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“…There is strong evidence that miR-155-mediated suppression of SOCS1 has biological significance in infection and autoimmunity [60]. This interaction has for example been implicated in the reduction in LPS-induced liver injury and reduced TNFα production observed with a miR-155 inhibitor in a mouse model [61]. In other contexts, however, the effect of miR-155 on SOCS1 may in fact be protective.…”

Section: Discussionmentioning

confidence: 99%

Characterization of basal and lipopolysaccharide-induced microRNA expression in equine peripheral blood mononuclear cells using Next-Generation Sequencing

et al. 2017

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The innate immune response to lipopolysaccharide contributes substantially to the morbidity and mortality of gram-negative sepsis. Horses and humans share an exquisite sensitivity to lipopolysaccharide and thus the horse may provide valuable comparative insights into this aspect of the inflammatory response. MicroRNAs, small non-coding RNA molecules acting as post-transcriptional regulators of gene expression, have key roles in toll-like receptor signaling regulation but have not been studied in this context in horses. The central hypothesis of this study was that lipopolysaccharide induces differential microRNA expression in equine peripheral blood mononuclear cells in a manner comparable to humans. Illumina Next Generation Sequencing was used to characterize the basal microRNA transcriptome in isolated peripheral blood mononuclear cells from healthy adult horses, and to evaluate LPS-induced changes in microRNA expression in cells cultured for up to four hours. Selected expression changes were validated using quantitative reverse-transcriptase PCR. Only miR-155 was significantly upregulated by LPS, changing in parallel with supernatant tumor necrosis factor-α concentration. Eight additional microRNAs, including miR-146a and miR-146b, showed significant expression change with time in culture without a clear LPS effect. Target predictions indicated a number of potential immunity-associated targets for miR-155 in the horse, including SOCS1, TAB2 and elements of the PI3K signaling pathway, suggesting that it is likely to influence the acute inflammatory response to LPS. Gene alignment showed extensive conservation of the miR-155 precursor gene and associated promoter regions between horses and humans. The basal and LPS-stimulated microRNA expression pattern characterized here were similar to those described in human leukocytes. As well as providing a resource for further research into the roles of microRNAs in immune responses in horses, this will facilitate inter-species comparative study of the role of microRNAs in the inflammatory cascade during endotoxemia and sepsis.

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Inhibition of microRNA-155 relieves sepsis-induced liver injury through inactivating the JAK/STAT pathway

Cited by 32 publications

References 24 publications

Comprehensive Transcriptome Profiling of Peripheral Blood Mononuclear Cells from Patients with Sepsis

Comprehensive Transcriptome Profiling of Peripheral Blood Mononuclear Cells from Patients with Sepsis

IκK-16 decreases miRNA-155 expression and attenuates the human monocyte inflammatory response

Characterization of basal and lipopolysaccharide-induced microRNA expression in equine peripheral blood mononuclear cells using Next-Generation Sequencing

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