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Regulation of T cell gene expression by Halofuginone (HF)

ABSTRACT: T cell differentiation to the Th17 effector subset requires stimulation through the T cell and co-stimulatory receptors, together with cytokine stimulation by TGFb and IL-6. The small molecule halofuginone (HF) inhibits Th17 cell development and induces a pattern of stress-regulated gene expression that mimics amino acid starvation. We used global transcript profiling to ask how halofuginone modulates gene expression induced during T cell activaiton and Th17 differentiation Keywords: T cell activation/ differentiation timecourse

ORGANISM(S): Mus musculus

PROVIDER: GSE15624 | GEO | 2009/04/10

SECONDARY ACCESSION(S): PRJNA116595

REPOSITORIES: GEO

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Transcription profiling of mouse T cells treated with halofuginone to investigate regulation of Y cell gene expression by Halofuginone (HF)

Project description:T cell differentiation to the Th17 effector subset requires stimulation through the T cell and co-stimulatory receptors, together with cytokine stimulation by TGFb and IL-6. The small molecule halofuginone (HF) inhibits Th17 cell development and induces a pattern of stress-regulated gene expression that mimics amino acid starvation. We used global transcript profiling to ask how halofuginone modulates gene expression induced during T cell activaiton and Th17 differentiation Experiment Overall Design: Purified mouse CD4+ CD25- T cells were activated under Th17 polarizing cytokine conditions and treated with either halofuginone or its inactive derivative, MAZ1310, for 3- or 6-hours.

2009-04-19 | E-GEOD-15624 | biostudies-arrayexpress

Transcriptional responses of wild-type and Gcn2-/- Th17 cells to halofuginone and rapamycin

Project description:This study was designed to evaluate similarities and differences between transcriptional responses of developing Th17 cells to the prolyl-tRNA synthetase inhibitor, halofuginone, and the mTOR inhibitor, rapamycin. Further comparisons between wild-type and Gcn2-/- Th17 cells allow for investigation into which gene modules regulated by halofuginone or rapamycin treatment require Gcn2. Murine CD4+ CD25- T cells were magnetically isolated from wild-type or Gcn2-/- T cells. These cells were activated through anti-CD3/ anti-CD28 antibodies and polarized into Th17 cells using TGFb plus IL-6. 10 nM halofuginone, 10 nM rapamycin, or vehicle control (DMSO) were added to cultures at the time of activation. Cells were harvested at 4, 18, or 72 hours post-activation and differentiation. RNA was isolated from each sample and used for microarray analysis. Each culture condition and time-point was repeated twice in independent experiments using cells isolated from different wild-type or Gcn2-/- mice. Vehicle versus halofuginone, vehicle versus rapamycin, halofuginone versus rapamycin. Gcn2-/- versus wild-type T cells treated with vehicle, halofuginone, or rapamycin.

2014-05-29 | E-GEOD-47478 | biostudies-arrayexpress

Microarray profiling reveals Integrated Stress Response is activated by Halofuginone in mammary epithelial cells

Project description:The small molecule Halofuginone (HF) is a potent regulator of extracellular matrix (ECM ) gene expression and is unique in its therapeutic potential. While the basis for HF effects is unknown, inhibition of TGFb signaling and activation of the AAR have been linked to HF transcriptional control of a number of ECM components and amelioration of fibrosis and alleviation of autoimmune disease by regulation of Th17 cell differentiation, respectively. The aim of this study was to generate a global expression profile of HF targets in epithelial cells to identify potential mediators of HF function in this cell type. We report that HF modulation of the ECM remodeling protein Mmp13 in epithelial cells is separable from previously reported effects of HF on TGFß signal inhibition, and use microarray expression analysis to correlate this with transcriptional responses characteristic of the Integrated Stress Response (ISR). Our findings suggest a common mechanism underlying HF anti-fibrotic and anti-angiogenic effects in parenchymal cells and HF effects on Th17 differentiation. Moreover, our results point away from a central role of TGFb signaling in the HF mechanism of action and suggest a new approach to small molecule based regulation of the ECM transcriptional program in vivo. NMuMG mammary epithelial cells were treated with 10 nM Halofuginone or 10 nM MAZ1310 (a non-functional analog of Halofuginone used as a control) for 8 hours. Each treatment was performed in biological triplicate. Following RNA extraction, we used Phalanx Mouse Whole Genome OneArray to measure mRNA abundance of Halofuginone-treated and MAZ1310 control samples. Each array was performed in triplicate. Expression of transcripts in Halofuginone versus MAZ1310 treated cells was examined.

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Transcriptional responses of wild-type and Gcn2-/- Th17 cells to halofuginone and rapamycin

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Proteome expression changes upon Halofuginone treatment

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2017-05-16 | PXD005679 | Pride

Microarray profiling reveals Integrated Stress Response is activated by Halofuginone in mammary epithelial cells

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Halofuginone is a potent inhibitor of SARS-CoV-2 Infection and Replication [Exp3]

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2023-08-28 | GSE166411 | GEO

Halofuginone is a potent inhibitor of SARS-CoV-2 Infection and Replication [Exp2]

Project description:Here we identify halofuginone, a Prolyl-tRNA Synthetase (PRS) inhibitors as a potent inhibitors of SARS-CoV-2 cellular entry and viral replication. To infect the host cell, the SARS-CoV-2 spike protein interacts with cell surface heparan sulfate (HS) and angiotensin-converting enzyme 2 (ACE2) through its Receptor Binding Domain. Removal of cell surface HS or blockade of HS biosynthesis represents a promising clinical target for treatment of SARS-CoV-2. In vitro studies confirm that halofuginone and PRS inhibitors prevent HS biosynthesis and thereby HS cell surface presentation and Spike protein binding. Halofuginone also suppresses authentic SARS-CoV-2 infection by inhibiting PRS activity, which decreases the translation efficiency of proline-rich HS biosynthetic enzymes and essential SARS-CoV-2 proteins after infection (data not provided here). Thus, halofuginone inhibits SARS-CoV-2 at both attachment and post-entry steps and blocks SARS-CoV-2 infection of human lung airway epithelial cells at low nanomolar concentrations. These findings support the use of halofuginone, an orally bioavailable anti-fibrotic and anti-inflammatory compound with encouraging clinical phase 1 safety data, as an antiviral drug to prevent SARS-CoV-2 infection.

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Halofuginone is a potent inhibitor of SARS-CoV-2 Infection and Replication [Exp1]

Project description:Here we identify halofuginone, a Prolyl-tRNA Synthetase (PRS) inhibitors as a potent inhibitors of SARS-CoV-2 cellular entry and viral replication. To infect the host cell, the SARS-CoV-2 spike protein interacts with cell surface heparan sulfate (HS) and angiotensin-converting enzyme 2 (ACE2) through its Receptor Binding Domain. Removal of cell surface HS or blockade of HS biosynthesis represents a promising clinical target for treatment of SARS-CoV-2. In vitro studies confirm that halofuginone and PRS inhibitors prevent HS biosynthesis and thereby HS cell surface presentation and Spike protein binding. Halofuginone also suppresses authentic SARS-CoV-2 infection by inhibiting PRS activity, which decreases the translation efficiency of proline-rich HS biosynthetic enzymes and essential SARS-CoV-2 proteins after infection (data not provided here). Thus, halofuginone inhibits SARS-CoV-2 at both attachment and post-entry steps and blocks SARS-CoV-2 infection of human lung airway epithelial cells at low nanomolar concentrations. These findings support the use of halofuginone, an orally bioavailable anti-fibrotic and anti-inflammatory compound with encouraging clinical phase 1 safety data, as an antiviral drug to prevent SARS-CoV-2 infection.

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Transcriptomic profiling of normal human cardiac fibroblast treated with halofuginone

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