ArticleThe Journal of experimental medicine2014
Rapamycin antagonizes TNF induction of VCAM-1 on endothelial cells by inhibiting mTORC2.
Article in The Journal of experimental medicine, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 70 citations in OpenAlex.
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- Cytokines from SARS-CoV-2 Spike-Activated Macrophages Hinder Proliferation and Cause Cell Dysfunction in Endothelial Cells.Biomolecules · 2024Article
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- Discovery of common molecular signatures and drug repurposing for COVID-19/Asthma comorbidity: ACE2 and multi-partite networks.Cell cycle (Georgetown, Tex.) · 2024Article
- Aging modulates homeostatic leukocyte trafficking to the peritoneal cavity in a sex-specific manner.Journal of leukocyte biology · 2023Article
- HLA class II antibody activation of endothelial cells induces M2 macrophage differentiation in peripheral blood.Clinical and experimental nephrology · 2023Article
- Role of mitochondrial metabolism in immune checkpoint inhibitors-related myocarditis.Frontiers in cardiovascular medicine · 2023Article
- High-Dimensional Cytometry Dissects Immunological Fingerprints of Idiopathic Inflammatory Myopathies.Cells · 2022Article
- Modulation of Xenogeneic T-cell Proliferation by B7 and mTOR Blockade of T Cells and Porcine Endothelial Cells.Transplantation · 2022Article
- Editorial: New biomarkers for the diagnosis and treatment of systemic lupus erythematosus.Frontiers in immunology · 2022Article
- High Magnesium and Sirolimus on Rabbit Vascular Cells-An In Vitro Proof of Concept.Materials (Basel, Switzerland) · 2021Article
- Mechanistic Target of Rapamycin Inhibitors in Renal Cell Carcinoma: Potential, Limitations, and Perspectives.Frontiers in cell and developmental biology · 2021Review
- Vascular Endothelial Senescence: Pathobiological Insights, Emerging Long Noncoding RNA Targets, Challenges and Therapeutic Opportunities.Frontiers in physiology · 2021Review
- PTH(1‑34) activates the migration and adhesion of BMSCs through the rictor/mTORC2 pathway.International journal of molecular medicine · 2020Article
- Rapamycin promotes endothelial-mesenchymal transition during stress-induced premature senescence through the activation of autophagy.Cell communication and signaling : CCS · 2020Article
- IRF-1 mediates the suppressive effects of mTOR inhibition on arterial endothelium.Journal of molecular and cellular cardiology · 2020Article
- A Novel STAT3-Mediated GATA6 Pathway Contributes toOxidative medicine and cellular longevity · 2020Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 2 countries.
Funding
Abstract
Recruitment of circulating leukocytes into inflamed tissues depends on adhesion molecules expressed by endothelial cells (ECs). Here we report that rapamycin pretreatment reduced the ability of TNF-treated ECs to capture T cells under conditions of venular flow. This functional change was caused by inhibition of TNF-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and could be mimicked by knockdown of mammalian target of rapamycin (mTOR) or rictor, but not raptor, implicating mTORC2 as the target of rapamycin for this effect. Mechanistically, mTORC2 acts through Akt to repress Raf1-MEK1/2-ERK1/2 signaling, and inhibition of mTORC2 consequently results in hyperactivation of ERK1/2. Increased ERK1/2 activity antagonizes VCAM-1 expression by repressing TNF induction of the transcription factor IRF-1. Preventing activation of ERK1/2 reduced the ability of rapamycin to inhibit TNF-induced VCAM-1 expression. In vivo, rapamycin inhibited mTORC2 activity and potentiated activation of ERK1/2. These changes correlated with reduced endothelial expression of TNF-induced VCAM-1, which was restored via pharmacological inhibition of ERK1/2. Functionally, rapamycin reduced infiltration of leukocytes into renal glomeruli, an effect which was partially reversed by inhibition of ERK1/2. These data demonstrate a novel mechanism by which rapamycin modulates the ability of vascular endothelium to mediate inflammation and identifies endothelial mTORC2 as a potential therapeutic target.
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