Transcriptional effects of catalytic mTOR inhibiton among LPS-stimulated primary human monocytes
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE187403 | GEO | 2022/07/29
REPOSITORIES: GEO
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2023-05-02 | PXD041927 | Pride
Project description:Sepsis is a severe and dysregulated inflammatory disease that often precedes the development of acute kidney injury (AKI) with consequent worsening outcome. The main characteristics of sepsis-induced AKI include endothelial cell (EC) dysfunction, infiltration of inflammatory cells, glomerular thrombosis, and renal tubular epithelial cells (RTEC) injury. Numerous studies have demonstrated that mammalian target of rapamycin (mTOR) activation has been implicated in the initiation and progression of renal injury in course of sepsis. However, little is known, about the molecular basis of mTOR role in EC and RTEC dysfunction. Here, we evaluate whether mTOR inhibition by Rapamycin (Rp) as potential strategy to ameliorate renal function and dissected the molecular mechanisms involved. In a mouse model of lipopolysaccharide (LPS)-induced AKI , LPS injection led to a time-dependent increase of serum creatinine and significant morphological changes in renal parenchyma associated with increased collagen deposits and endothelial dysfunction. Interestingly, Rp treatment significantly decreased creatine levels and preserved renal parenchyma, counteracting Endothelial-to mesenchymal transition (EndMT) process and early fibrosis through the inhibition of ERK pathway. Next, we examined the effects of LPS-TLR4 interaction in RTECs. Through a whole-genome DNA methylation analysis in cultured RTEC, we found that LPS induced aberrant methylation, particularly in regions involved in premature aging. The most represented genes were CD39 and WFS1. LPS stimulation of RTEC led to up-regulation of SA-β Gal and cell cycle arrest markers such as p21. In accordance, in endotoxemic mice, we found a decreased expression of CD39 concurrent with Klotho down-regulation. Administration of Rp exerted anti-aging effects in endotoxemic mice, preserving CD39 and Klotho expression. In conclusion, we demonstrated that mTOR inhibition could offer novel strategies to protect endothelial and tubular compartment from accelerated aging and fibrosis thus counteracting the progression to chronic kidney disease.
2024-09-16 | E-MTAB-13396 | biostudies-arrayexpress
Project description:We report mTOR inhibitor (mTORi) is synergistic with BET inhibitor (BETi) in controlling tumor growth and inducing apoptosis in small cell lung cancer (SCLC) patient-derived xenograft (PDX) models. In this study, we studied impact of different treatment on whole-genome mRNA transcriptome in SCLC PDX tumors. Four different treatments (vehicle control, NHWD870 [BETi; 1.5mg/kg], everolimus [mTORi; 2mg/kg], and the combo [NHWD870 1mg/kg and everolimus 1.5mg/kg] were administered daily for one week in a small cell lung cancer PDX LX-95 model. Tumor cells were isolated from PDX tumors using a magnetic-activated cell sorting method to enrich human tumor cells and total RNA was extracted using the RNeasy Mini Kit (Qiagen). mRNA libraries were constructed and pair-ended sequenced using Illumina high-throughput sequencing technology. The length of sequence reads was 150 bp.The samples have 12 to 129 million pass filter reads with more than 90% of bases above the quality score of Q30. We found BET inhibitor increases expression of RPS6KA2, a gene that mediates crosstalk between MAPK and mTOR pathway.
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Project description:Type-I interferon (IFN)-induced activation of the mammalian target of rapamycin (mTOR) signaling pathway has been implicated in translational control of mRNAs encoding interferon-stimulated genes (ISGs). However, mTOR-sensitive translatomes commonly include mRNAs with a 5’ terminal oligopyrimidine tract (TOP), such as those encoding ribosomal proteins, but not ISGs. Because these translatomes were obtained under conditions when ISG expression is not induced, we examined the mTOR-sensitive translatome in human WISH cells stimulated with IFNβ. The mTOR inhibitor Torin1 resulted in a repression of global protein synthesis, including that of ISG products, and translation of all but 3 ISG mRNAs (TLR3, NT5C3A, and RNF19B) was not selectively more sensitive to mTOR inhibition. Detailed studies of NT5C3A revealed an IFN-induced change in transcription start site resulting in a switch from a non-TOP to a TOP-like transcript variant and mTOR sensitive translation. Thus, we show that, in the cell model used, translation of the vast majority of ISG mRNAs is not selectively sensitive to mTOR activity and describe an uncharacterized mechanism wherein the 5’-UTR of an mRNA is altered in response to a cytokine, resulting in a shift from mTOR-insensitive to mTOR-sensitive translation.
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Project description:Monocytes are a distinct subset of myeloid cells with diverse functions in early inflammatory immune modulation. While previous studies have surveyed the role of miRNA regulation on different myeloid cell lines and primary cultures, the time-dependent kinetics of inflammatory stimulation on miRNA expression and the relationship between miRNA-to-target RNA expression have not been comprehensively profiled in monocytes. In this study, we use next-generation sequencing and RT-PCR assays to analyze the non-coding small RNA transcriptome of unstimulated and lipopolysaccharide (LPS)-stimulated monocytes at 6 and 24 hours. We identified a miRNA signature consisting of five mature miRNAs (hsa-mir-146a, hsa-mir-155, hsa-mir-9, hsa-mir-147b, and hsa-mir-193a) upregulated by LPS-stimulated monocytes after 6 hours and found that most miRNAs were also upregulated after 24 hours of stimulation. Only one miRNA gene was down-regulated and no other small RNAs were found dysregulated in monocytes after LPS treatment. In addition, novel tRNA-derived fragments were also discovered in monocytes although none showed significant changes upon LPS stimulation. Interrogation of validated miRNA targets by transcriptomic analysis revealed that absolute expression of most miRNA targets implicating in innate immune response decreased over time in LPS-stimulated monocytes although their expression patterns along the treatment were heterogeneous. Our findings reveal a potential role by which selective miRNA upregulation and stable expression of other small RNAs enable monocytes to develop finely tuned cellular responses during acute inflammation.
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Project description:To further develop our gene expression approach to treatment of autoimmunity, we have employed whole genome microarray expression profiling as a discovery platform to identify genes differentially expressed upon immunosuppressor treatment responsible for inhibition of T cell effector functions. Human CD4+CD25- cells from healthy donors were pretreated or not with rapamycin and stimulated with anti-CD3 and anti-CD28 for 12h. mTOR (Mammalian Target of Rapamycin) inhibition-induced gene expression was evaluated in human effector T cells after 1 hour rapamycin pretreatment and compared to vehicle-pretreated cells. Three independent experiments were performed for each of the two different experimental conditions using different donors for each experiment.
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