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Vasodilation of Isolated Vessels and the Isolation of the Extracellular Matrix of Tight-skin Mice
Published on: March 24, 2017
IRF-1 Links Cytoskeletal Contraction With Inflammatory Response in mTOR-Inhibited Endothelial Cells.
Ying Zhou1,2, Zhiyang Zhang1,2, Chengxiu Hu1,2
1Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China.
Summary
Mammalian target of rapamycin inhibition (mTORi) causes lung inflammation by upregulating interferon regulatory factor-1 (IRF-1) in endothelial cells. IRF-1 activation promotes endothelial hyperpermeability and lung injury.
Area of Science:
- Cell Biology
- Immunology
- Pharmacology
Background:
- Mammalian target of rapamycin (mTOR) inhibitors are linked to pneumonitis.
- mTOR inhibition (mTORi) upregulates the proinflammatory transcription factor interferon regulatory factor-1 (IRF-1) in endothelial cells (EC).
- mTORi-induced EC cytoskeletal changes promote hyperpermeability and pulmonary inflammation.
Purpose of the Study:
- Investigate the mechanism linking IRF-1 expression to downstream responses in mTOR-inhibited EC.
- Elucidate the role of IRF-1 in mTORi-induced endothelial hyperpermeability and lung inflammation.
Main Methods:
- Treatment of cultured EC with mTOR inhibitors (rapamycin, torin 1) or genetic disruption of mTORC1/mTORC2.
- Assessment of IRF-1 expression, cytokine transcription, and myosin light chain (MLC) phosphorylation.
- Inhibition of MLC kinase (MLCK), activation of MLC phosphatase (MLCP), or actin polymerization inhibition.
- Evaluation of endothelial hyperpermeability.
- Analysis of lung edema and inflammation in mice with targeted endothelial IRF-1 deficiency.
Main Results:
- mTOR inhibition upregulated IRF-1 transcription in EC.
- Inhibition of MLCK, MLCP activation, or actin polymerization attenuated IRF-1 and proinflammatory cytokine expression.
- IRF-1 upregulated MLCK, enhancing MLC phosphorylation and EC hyperpermeability.
- Endothelial IRF-1 deficiency in mice reduced rapamycin/lipopolysaccharide-induced lung edema and inflammation.
Conclusions:
- mTOR inhibition activates actomyosin contractility, upregulating IRF-1 in EC.
- Upregulated IRF-1 mediates EC inflammation and hyperpermeability, contributing to mTORi-induced lung injury.
Keywords:
actin cytoskeletoncell contractionendothelial cellinflammationlung injurymTOR inhibitionmyosin light chainpermeabilityMore Related Videos
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